75 results on '"t(4"'
Search Results
2. Prognostic value of t(4;14) translocation in newly diagnosed multiple myeloma patients in novel agent era.
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Geng, Chuanying, Yang, Guangzhong, Zhou, Huixing, Wang, Huijuan, Li, Yanchen, Leng, Yun, Zhang, Zhiyao, Jian, Yuan, and Chen, Wenming
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MULTIPLE myeloma , *PROGNOSIS , *PROPENSITY score matching , *PROGRESSION-free survival , *OVERALL survival - Abstract
To evaluate the prognostic value of t(4; 14) translocation for newly diagnosed multiple myeloma (MM) patients in the novel agent era. We retrospectively analyzed 606 newly diagnosed MM patients treated with novel agents. The propensity score matching technique was used to reduce the bias between groups. Among 606 patients, t(4; 14) was observed in 108 (17.8%) patients, among which 79 (73.1%) were accompanied by 1q21 gain and/or del 17p. Median overall survival (OS) (56.2 vs. 87.3 months) and progression-free survival (PFS) (25.7 vs. 37.6 months) were significantly shorter in patients with t(4;14) compared with patients without cytogenetic abnormalities. Univariate Cox proportional hazards regression analysis showed that the t(4;14) was not associated with shorter OS (p = 0.666) and PFS (p = 0.164). The multivariable analysis also showed t(4;14) was not a poor prognostic factor for OS and PFS of patients with newly diagnosed MM (p > 0.05). After balancing the distribution of factors between patients with and without t(4;14) by the propensity score matching technique, patients with t(4;14) had similar OS (57.6 vs. 56.5 months, p = 0.964) and PFS (26.5 vs. 28.1 months, p = 0.740) with the patients without t(4;14). These results demonstrated that t(4; 14) alone may be not a poor prognostic factor patients with newly diagnosed MM in the novel agent era. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Prognostic value of t(4;14) translocation in newly diagnosed multiple myeloma patients in novel agent era
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Chuanying Geng, Guangzhong Yang, Huixing Zhou, Huijuan Wang, Yanchen Li, Yun Leng, Zhiyao Zhang, Yuan Jian, and Wenming Chen
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Multiple myeloma ,t(4 ,14) translocation ,survival ,prognostic factors ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
ABSTRACTObjective To evaluate the prognostic value of t(4; 14) translocation for newly diagnosed multiple myeloma (MM) patients in the novel agent era.Methods We retrospectively analyzed 606 newly diagnosed MM patients treated with novel agents. The propensity score matching technique was used to reduce the bias between groups.Results Among 606 patients, t(4; 14) was observed in 108 (17.8%) patients, among which 79 (73.1%) were accompanied by 1q21 gain and/or del 17p. Median overall survival (OS) (56.2 vs. 87.3 months) and progression-free survival (PFS) (25.7 vs. 37.6 months) were significantly shorter in patients with t(4;14) compared with patients without cytogenetic abnormalities. Univariate Cox proportional hazards regression analysis showed that the t(4;14) was not associated with shorter OS (p = 0.666) and PFS (p = 0.164). The multivariable analysis also showed t(4;14) was not a poor prognostic factor for OS and PFS of patients with newly diagnosed MM (p > 0.05). After balancing the distribution of factors between patients with and without t(4;14) by the propensity score matching technique, patients with t(4;14) had similar OS (57.6 vs. 56.5 months, p = 0.964) and PFS (26.5 vs. 28.1 months, p = 0.740) with the patients without t(4;14).Conclusions These results demonstrated that t(4; 14) alone may be not a poor prognostic factor patients with newly diagnosed MM in the novel agent era.
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- 2023
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4. IGH::NSD2 Fusion Gene Transcript as Measurable Residual Disease Marker in Multiple Myeloma
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András Bors, András Kozma, Ágnes Tomán, Zoltán Őrfi, Nóra Kondor, Szabolcs Tasnády, István Vályi-Nagy, Péter Reményi, Gábor Mikala, and Hajnalka Andrikovics
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multiple myeloma ,measurable residual disease ,real-time PCR ,digital PCR ,t(4 ,14) ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Multiple myeloma (MM) is the second most common hematological malignancy. Approximately 15% of MM patients are affected by the t(4;14) translocation resulting in the IGH::NSD2 fusion transcript. Breakage occurs in three major breakpoint regions within the NSD2 gene (MB4-1, MB4-2, and MB4-3), where MB4-1 leads to the production of full-length protein, while truncated proteins are expressed in the other two cases. Measurable residual disease (MRD) has been conclusively established as a crucial prognostic factor in MM. The IGH::NSD2 fusion transcript can serve as a sensitive MRD marker. Using bone marrow (BM) and peripheral blood (PB) samples from 111 patients, we developed a highly sensitive quantitative real-time PCR (qPCR) and digital PCR (dPCR) system capable of detecting fusion mRNAs with a sensitivity of up to 1:100,000. PB samples exhibited sensitivity three orders of magnitude lower compared to BM samples. Patients with an MB4-2 breakpoint demonstrated significantly reduced overall survival (p = 0.003). Our novel method offers a simple and sensitive means for detecting MRD in a substantial proportion of MM patients. Monitoring may be carried out even from PB samples. The literature lacks consensus regarding survival outcomes among patients with different NSD2 breakpoints. Our data align with previous findings indicating that patients with the MB4-2 breakpoint type tend to exhibit unfavorable overall survival.
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- 2024
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5. A minority of cases of acinic cell carcinoma of the salivary glands are driven by an NR4A2 rearrangement: the diagnostic utility of the assessment of NR4A2 and NR4A3 alterations in salivary gland tumors.
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Klubíčková, Natálie, Grossmann, Petr, Šteiner, Petr, Baněčková, Martina, Mosaieby, Elaheh, Koshyk, Olena, Michal, Michal, Leivo, Ilmo, and Skálová, Alena
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Acinic cell carcinoma (AciCC) is a common salivary gland malignancy, typically composed of neoplastic acinic cells with zymogen granules. The vast majority of cases are driven by a t(4;9)(q13;q31) leading to enhancer hijacking and upregulation of the NR4A3 gene. However, a minority of cases do not display NR4A3 overexpression on immunohistochemical examination and are negative for the rearrangement involving the NR4A3 gene when tested by FISH. Such cases overexpress NR4A2, and the protein product is detectable by immunohistochemistry. In this study, we aimed to assess the utility of NR4A2 and NR4A3 immunohistochemistry in the differential diagnosis of salivary gland tumors. Eighty-five cases of classic low-grade ACiCC, as well as 36 cases with high-grade transformation (HGT) and 7 high-grade AciCC cases were included in the analysis. NR4A3 was at least focally positive in 105/128 (82%) cases. Out of the 23 cases that were immunohistochemically negative for NR4A3, 6 displayed nuclear immunopositivity with the NR4A2 antibody. The NR4A3 rearrangement was confirmed by FISH in 38/52 (73%) cases. In addition, this is the first report of an NR4A2 rearrangement being detected by FISH in 2 AciCC cases that were negative for the NR4A3 rearrangement. Our analysis confirms that the majority of AciCC, including high-grade cases and cases with HGT, are immunopositive for NR4A3, and suggests that NR4A3 immunohistochemistry is a powerful tool in the differential diagnosis of salivary gland tumors. However, its utility is limited in sub-optimally fixed samples which often display weaker and focal positivity. Our study also indicates that in a minority of cases, AciCC might be negative for NR4A3 immunostaining, because the pathogenic genetic event in these cases is instead a rearrangement involving the NR4A2 gene. [ABSTRACT FROM AUTHOR]
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- 2023
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6. A unique three-way Philadelphia chromosome variant t(4;9;22)(q21;q34;q11.2) in a newly diagnosed patient with chronic phase chronic myeloid leukemia: a case report and review of the literature
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Yuka Torii, Kana Nanjo, Tomomi Toubai, Masashi Hosokawa, Ryo Sato, Akane Yamada, Keiko Aizawa, Masahito Himuro, Satoshi Ito, Masakazu Yamamoto, John Magenau, Ryan Wilcox, and Kenichi Ishizawa
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t(4 ,22)(q21 ,Q34 ,Q11.2) ,CML ,Philadelphia chromosome ,Three-way variant ,Medicine - Abstract
Abstract Background Chronic myeloid leukemia is a hematologic malignancy associated with the fusion of two genes: BCR and ABL1. This fusion results from a translocation between chromosomes 9 and 22, which is called the Philadelphia chromosome. Although the Philadelphia chromosome is present in more than 90% of patients with chronic myeloid leukemia, 5–8% of patients with chronic myeloid leukemia show complex variant translocations. Herein, we report a unique case of a three-way translocation variant in chronic phase chronic myeloid leukemia. Case presentation A 40-year-old Asian male who presented with leukocytosis was diagnosed with chronic phase chronic myeloid leukemia. Cytogenetic karyotyping analysis showed 46,XY,t(4;9;22)(q21;q34;q11.2). He was treated with bosutinib and then changed to dasatinib because of intolerance, and MR4.5 (BCR-ABL/ABL ≦ 0.0032%, international scale) was achieved after 17 months of continuous treatment. Conclusion This was the 14th case of t(4;9;22), in particular, a new variant Ph translocation involved in chromosome 4q21 and the first successful case treated with tyrosine kinase inhibitors in the world. We summarize previous case reports regarding three-way variant chromosome translocation, t(4;9;22) and discuss how this rare translocation is linked to prognosis.
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- 2021
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7. Case of Patient with AML with Complex Karyotype including Ultra-Rare t(4;8)(q32;q13), t(4;11)(q21;p15) and Familial Aggregation of Myeloid Malignancies
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Sławomir Milczarek, Ewa Studniak, Bartłomiej Baumert, Michał Janowski, Wioleta Bonda, Joanna Pietrzak, Aleksandra Łanocha, Edyta Paczkowska, Barbara Zdziarska, and Bogusław Machaliński
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AML ,t(4 ,8)(q32 ,q13) ,11)(q21 ,q15) ,familial aggregation ,MPN ,Medicine (General) ,R5-920 - Abstract
We present a unique case of a young woman with acute myeloid leukemia (AML) with complex karyotype. The presence of the t(4;11)(q23;p15) is extremely rare in myeloid leukemias, while t(4;8)(q32;q13) has not yet been described in any leukemia reference. Another interesting issue is the familial aggregation of myeloid malignancies and worse course of the disease in each subsequent generation, as well as an earlier onset of the disease. Our report emphasizes the need for thorough pedigree examination upon myeloid malignancy diagnosis as there are relatives for whom counseling, gene testing, and surveillance may be highly advisable.
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- 2022
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8. IGH::NSD2 Fusion Gene Transcript as Measurable Residual Disease Marker in Multiple Myeloma.
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Bors A, Kozma A, Tomán Á, Őrfi Z, Kondor N, Tasnády S, Vályi-Nagy I, Reményi P, Mikala G, and Andrikovics H
- Abstract
Multiple myeloma (MM) is the second most common hematological malignancy. Approximately 15% of MM patients are affected by the t(4;14) translocation resulting in the IGH::NSD2 fusion transcript. Breakage occurs in three major breakpoint regions within the NSD2 gene (MB4-1, MB4-2, and MB4-3), where MB4-1 leads to the production of full-length protein, while truncated proteins are expressed in the other two cases. Measurable residual disease (MRD) has been conclusively established as a crucial prognostic factor in MM. The IGH::NSD2 fusion transcript can serve as a sensitive MRD marker. Using bone marrow (BM) and peripheral blood (PB) samples from 111 patients, we developed a highly sensitive quantitative real-time PCR (qPCR) and digital PCR (dPCR) system capable of detecting fusion mRNAs with a sensitivity of up to 1:100,000. PB samples exhibited sensitivity three orders of magnitude lower compared to BM samples. Patients with an MB4-2 breakpoint demonstrated significantly reduced overall survival ( p = 0.003). Our novel method offers a simple and sensitive means for detecting MRD in a substantial proportion of MM patients. Monitoring may be carried out even from PB samples. The literature lacks consensus regarding survival outcomes among patients with different NSD2 breakpoints. Our data align with previous findings indicating that patients with the MB4-2 breakpoint type tend to exhibit unfavorable overall survival.
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- 2024
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9. Resveratrol given intraperitoneally does not inhibit the growth of high-risk t(4;11) acute lymphoblastic leukemia cells in a NOD/SCID mouse model
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ZUNINO, SUSAN J, STORMS, DAVID H, NEWMAN, JOHN W, PEDERSEN, THERESA L, KEEN, CARL L, and DUCORE, JONATHAN M
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Hematology ,Rare Diseases ,Complementary and Integrative Health ,Pediatric Cancer ,Pediatric ,Childhood Leukemia ,Cancer ,Animals ,Anticarcinogenic Agents ,Antineoplastic Agents ,Phytogenic ,Disease Models ,Animal ,Female ,Humans ,Infusions ,Parenteral ,Mice ,Mice ,Inbred NOD ,Mice ,SCID ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Resveratrol ,Stilbenes ,t(4 ,11) acute lymphoblastic leukemia ,resveratrol ,vincristine ,metabolites ,NOD/SCID mice ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
The efficacy of resveratrol as a preventive agent against the growth of t(4;11) acute lymphoblastic leukemia (ALL) was evaluated in NOD.CB17-Prkdcscid/J mice engrafted with the human t(4;11) ALL SEM cell line. SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry. Once engraftment was observed, mice were injected intraperitoneally with resveratrol (10 mg/kg body weight) dissolved in dimethylsulfoxide (DMSO) or DMSO alone (control) every other day, or vincristine (0.5 mg/kg body weight) 3 times per week for 4 weeks (n=16 per group). Comparisons of the percent of human leukemia cells in blood and survival curves showed resveratrol did not inhibit progression of the disease. Liquid chromatography-tandem mass spectrometry analyses of mouse sera showed resveratrol was rapidly metabolized to glucuronidated and sulfated forms 1 h post-injection, with low to no resveratrol or metabolites observed in sera by 24-48 h. These data indicate that in contrast to findings in in vitro models, parenterally administered resveratrol does not have potential as a preventive agent against high risk t(4;11) ALL.
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- 2012
10. A variant of acute promyelocytic leukemia with t(4;17)(q12;q21) showed two different clinical symptoms
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Takahisa Nakanishi, Aya Nakaya, Yusuke Nishio, Shinya Fujita, Atsushi Satake, Yoshiko Azuma, Yukie Tsubokura, Ryo Saito, Akiko Konishi, Masaaki Hotta, Hideaki Yoshimura, Yoshihiko Kadosaka, Kazuyoshi Ishii, Tomoki Ito, Koji Tsuta, and Shosaku Nomura
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acute promyelocytic leukemia ,t(4 ,17)(q12 ,q21) ,PML-RARA ,all-trans retinoic acid ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
A 63-year-old man was diagnosed with a rare variant of acute promyelocytic leukemia (APL) with t(4;17)(q12; q21) that showed atypical morphological features and two different clinical symptoms. He was started on standard induction chemotherapy for acute myeloid leukemia, which decreased myeloblast numbers; however, APL-like blasts remained. He then received a salvage therapy that added all-trans retinoic acid (ATRA). After ATRA commenced, APL-like blasts disappeared and cytogenetic analysis became normal. However, myeloblasts subsequently increased, and he became resistant. In summary, this patient exhibited two different clinical courses of acute myeloid leukemia and APL.
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- 2019
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11. Myeloid malignancies with translocation t(4;12)(q11‐13;p13): molecular landscape, clonal hierarchy and clinical outcomes
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François Lifermann, Jean-Alain Martignoles, Anne Quinquenel, Vincent Parinet, Christine Lefebvre, Pierre Hirsch, Mélanie Martin, Sabine Defasque, Florence Nguyen-Khac, Matthieu Decamp, Laurence Simon, Dominique Penther, Nadia Ali-Ammar, Elise Chapiro, Odile Maarek, Chrystele Bilhou-Nabera, Baptiste Gaillard, Agathe Maillon, Jean-Baptiste Micol, Marine Baron, Nathalie Auger, Stéphanie Struski, Damien Roos-Weil, Sylvie Tondeur, Marie-Joelle Mozziconacci, Audrey Bidet, Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Robert Debré, Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire CERBA [Saint Ouen l'Aumône], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Hospitalier de Dax, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Service d'immunologie et hématologies biologiques [CHU Saint-Antoine], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), HAL-SU, Gestionnaire, École Pratique des Hautes Études (EPHE), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Male ,Oncology ,Myeloid ,[SDV]Life Sciences [q-bio] ,Chromosomal translocation ,Translocation, Genetic ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,12) ,In Situ Hybridization, Fluorescence ,Aged, 80 and over ,CHIC2 ,Middle Aged ,Immunohistochemistry ,3. Good health ,[SDV] Life Sciences [q-bio] ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,RUNX1 ,030220 oncology & carcinogenesis ,Cytogenetic Analysis ,Cohort ,Molecular Medicine ,Female ,Original Article ,Chromosomes, Human, Pair 4 ,medicine.medical_specialty ,IDH1 ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Genetic Predisposition to Disease ,acute myeloid leukaemia ,Genetic Association Studies ,Aged ,Chromosome Aberrations ,Chromosomes, Human, Pair 12 ,Myeloproliferative Disorders ,business.industry ,Myelodysplastic syndromes ,Original Articles ,ETV6 ,Cell Biology ,medicine.disease ,myelodysplastic syndrome ,t(4 ,chemistry ,Fusion transcript ,Myelodysplastic Syndromes ,prognosis ,business ,030215 immunology - Abstract
International audience; Translocation t(4;12)(q11-13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56–88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.
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- 2021
12. Unraveling the Activation Mechanism of Taspase1 which Controls the Oncogenic AF4–MLL Fusion Protein
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Samaneh Sabiani, Tim Geppert, Christian Engelbrecht, Eric Kowarz, Gisbert Schneider, and Rolf Marschalek
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t(4 ,11) leukemia ,Taspase1 ,AF4–MLL ,Oncoprotein activation ,Medicine ,Medicine (General) ,R5-920 - Abstract
We have recently demonstrated that Taspase1-mediated cleavage of the AF4–MLL oncoprotein results in the formation of a stable multiprotein complex which forms the key event for the onset of acute proB leukemia in mice. Therefore, Taspase1 represents a conditional oncoprotein in the context of t(4;11) leukemia. In this report, we used site-directed mutagenesis to unravel the molecular events by which Taspase1 becomes sequentially activated. Monomeric pro-enzymes form dimers which are autocatalytically processed into the enzymatically active form of Taspase1 (αββα). The active enzyme cleaves only very few target proteins, e.g., MLL, MLL4 and TFIIA at their corresponding consensus cleavage sites (CSTasp1) as well as AF4–MLL in the case of leukemogenic translocation. This knowledge was translated into the design of a dominant-negative mutant of Taspase1 (dnTASP1). As expected, simultaneous expression of the leukemogenic AF4–MLL and dnTASP1 causes the disappearance of the leukemogenic oncoprotein, because the uncleaved AF4–MLL protein (328 kDa) is subject to proteasomal degradation, while the cleaved AF4–MLL forms a stable oncogenic multi-protein complex with a very long half-life. Moreover, coexpression of dnTASP1 with a BFP-CSTasp1-GFP FRET biosensor effectively inhibits cleavage. The impact of our findings on future drug development and potential treatment options for t(4;11) leukemia will be discussed.
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- 2015
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13. Acute myeloid leukemia with t(4;12)(q12;p13): A morphological dilemma
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Umang V Patel, S R Arun, Deepak Kumar Mishra, and Mayur Parihar
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Acute myeloid leukemia ,dysplasia ,pseudo lymphoid morphology ,t(4 ,12) ,Pathology ,RB1-214 ,Microbiology ,QR1-502 - Abstract
Cytogenetics has a pivotal role in risk stratification of acute myeloid leukemia (AML). We report a case of AML with a t(4;12)(q12;p13). To the best of our knowledge, there are about 24 cases of t(4;12) reported in AML which are usually misdiagnosed as lymphoproliferative disorders on morphological assessment. This case showed specific clinical, morphological, and immunophenotypic features such as (1) pseudo lymphoid morphology, (2) dysplasia in granulocytic series, (3) an immature immunophenotype with positivity for CD34 and CD117, and (4) poor treatment response.
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- 2016
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14. MiR‐27a downregulates 14‐3‐3θ, RUNX1, AF4, and MLL‐AF4, crucial drivers of blast transformation in t(4;11) leukemia cells
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Tiziana Fioretti, Mariateresa Zanobio, Maddalena Raia, Santa Errichiello, Barbara Izzo, Fabio Cattaneo, Rosario Ammendola, Armando Cevenini, Gabriella Esposito, Fioretti, Tiziana, Zanobio, Mariateresa, Raia, Maddalena, Errichiello, Santa, Izzo, Barbara, Cattaneo, Fabio, Ammendola, Rosario, Cevenini, Armando, and Esposito, Gabriella
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MLL ,AF4 ,Oncogene Proteins, Fusion ,microRNA ,target therapy ,Clinical Biochemistry ,Cell Biology ,General Medicine ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,MiR-27a ,Lymphocyte Activation ,Biochemistry ,MicroRNAs ,14-3-3θ ,t(4 ,Core Binding Factor Alpha 2 Subunit ,Humans ,11) acute leukemia ,Myeloid-Lymphoid Leukemia Protein - Abstract
The chromosomal translocation t(4;11)(q21;q23), a hallmark of an aggressive form of acute lymphoblastic leukemia (ALL), encodes mixed-lineage leukemia (MLL)-AF4 oncogenic chimera that triggers aberrant transcription of genes involved in lymphocyte differentiation, including HOXA9 and MEIS1. The scaffold protein 14-3-3θ, which promotes the binding of MLL-AF4 to the HOXA9 promoter, is a target of MiR-27a, a tumor suppressor in different human leukemia cell types. We herein study the role of MiR-27a in the pathogenesis of t(4;11) ALL. Reverse transcription quantitative PCR (qPCR) reveals that MiR-27a and 14-3-3θ expression is inversely correlated in t(4;11) ALL cell lines; interestingly, MiR-27a relative expression is significantly lower in patients affected by t(4;11) ALL than in patients affected by the less severe t(12;21) leukemia. In t(4;11) leukemia cells, ectopic expression of MiR-27a decreases protein level of 14-3-3θ and of the key transcription factor RUNX1. We show for the first time that MiR-27a also targets AF4 and MLL-AF4; in agreement, MiR-27a overexpression strongly reduces AF4 and MLL-AF4 protein levels in RS4;11 cells. Consequent to AF4 and MLL-AF4 downregulation, MiR-27a overexpression negatively affects transcription of HOXA9 and MEIS1 in different t(4;11) leukemia cell lines. In agreement, we show through chromatin immunoprecipitation experiments that MiR-27a overexpression impairs the binding of MLL-AF4 to the HOXA9 promoter. Lastly, we found that MiR-27a overexpression decreases viability, proliferation, and clonogenicity of t(4;11) cells, whereas it enhances their apoptotic rate. Overall, our study identifies the first microRNAthat strikes in one hit four crucial drivers of blast transformation in t(4;11) leukemia. Therefore, MiR-27a emerges as a new promising therapeutic target for this aggressive and poorly curable form of leukemia.
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- 2022
15. Predictive value of 1q21 gain in multiple myeloma is strongly dependent on concurrent cytogenetic abnormalities and first-line treatment
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Minguela, Alfredo, Vasco-Mogorron, Maria A., Campillo, Jose A., Cabanas, Valentin, Remigia, Maria J., Berenguer, Mercedes, Garcia-Garay, Maria C., Blanquer, Miguel, Cava, Catalina, Galian, Jose Antonio, Gimeno, Lourdes, Soto-Ramirez, Maria F., Martinez-Hernandez, Maria D., de la Rubia, Javier, Teruel, I, Ana, Muro, Manuel, and Periago, Adela
- Subjects
multiple myeloma ,t(4 ,autologous stem cell transplantation ,High-risk cytogenetic abnormalities ,1q21 gain, High-risk cytogenetic abnormalities, autologous stem cell transplantation, del(17p), immunomodulatory and proteasome inhibitor treatments, multiple myeloma, plasma cell neoplasm, t(4 ,immunomodulatory and proteasome inhibitor treatments ,del(17p) ,14) ,Original Article ,plasma cell neoplasm ,1q21 gain - Abstract
Improved therapies in multiple myeloma (MM) have forced a constant risk stratification update, first Durie-Salmon, then international scoring systems (ISS), next revised-ISS (RISS) including high-risk cytogenetic abnormalities (HRCAs) such as del(17p) and t(4;14), and now R2-ISS including 1q21 gain has been proposed. Predictive value of 1q21 gain by itself or in concurrence with other cytogenetic abnormalities is evaluated in 737 real-world plasma cell neoplasm (PCN) patients under current therapies. Ten-year progression-free survival (10y-PFS) rates for patients with 2, 3 and 3 copies of 1q21 were 72.2%, 42.5% and 43.4% (P
- Published
- 2021
16. A minority of cases of acinic cell carcinoma of the salivary glands are driven by an NR4A2 rearrangement: the diagnostic utility of the assessment of NR4A2 and NR4A3 alterations in salivary gland tumors.
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Klubíčková N, Grossmann P, Šteiner P, Baněčková M, Mosaieby E, Koshyk O, Michal M, Leivo I, and Skálová A
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- Humans, Salivary Glands pathology, Cell Nucleus pathology, Immunohistochemistry, Biomarkers, Tumor analysis, Nuclear Receptor Subfamily 4, Group A, Member 2 metabolism, DNA-Binding Proteins metabolism, Receptors, Thyroid Hormone metabolism, Carcinoma, Acinar Cell diagnosis, Carcinoma, Acinar Cell genetics, Carcinoma, Acinar Cell metabolism, Salivary Gland Neoplasms diagnosis, Salivary Gland Neoplasms genetics, Salivary Gland Neoplasms pathology, Receptors, Steroid genetics
- Abstract
Acinic cell carcinoma (AciCC) is a common salivary gland malignancy, typically composed of neoplastic acinic cells with zymogen granules. The vast majority of cases are driven by a t(4;9)(q13;q31) leading to enhancer hijacking and upregulation of the NR4A3 gene. However, a minority of cases do not display NR4A3 overexpression on immunohistochemical examination and are negative for the rearrangement involving the NR4A3 gene when tested by FISH. Such cases overexpress NR4A2, and the protein product is detectable by immunohistochemistry. In this study, we aimed to assess the utility of NR4A2 and NR4A3 immunohistochemistry in the differential diagnosis of salivary gland tumors. Eighty-five cases of classic low-grade ACiCC, as well as 36 cases with high-grade transformation (HGT) and 7 high-grade AciCC cases were included in the analysis. NR4A3 was at least focally positive in 105/128 (82%) cases. Out of the 23 cases that were immunohistochemically negative for NR4A3, 6 displayed nuclear immunopositivity with the NR4A2 antibody. The NR4A3 rearrangement was confirmed by FISH in 38/52 (73%) cases. In addition, this is the first report of an NR4A2 rearrangement being detected by FISH in 2 AciCC cases that were negative for the NR4A3 rearrangement. Our analysis confirms that the majority of AciCC, including high-grade cases and cases with HGT, are immunopositive for NR4A3, and suggests that NR4A3 immunohistochemistry is a powerful tool in the differential diagnosis of salivary gland tumors. However, its utility is limited in sub-optimally fixed samples which often display weaker and focal positivity. Our study also indicates that in a minority of cases, AciCC might be negative for NR4A3 immunostaining, because the pathogenic genetic event in these cases is instead a rearrangement involving the NR4A2 gene., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2023
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17. A unique three-way Philadelphia chromosome variant t(4;9;22)(q21;q34;q11.2) in a newly diagnosed patient with chronic phase chronic myeloid leukemia: a case report and review of the literature
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Masakazu Yamamoto, Kana Nanjo, Ryo Sato, John M. Magenau, Keiko Aizawa, Masashi Hosokawa, Tomomi Toubai, Yuka Torii, Akane Yamada, Kenichi Ishizawa, Ryan A. Wilcox, Masahito Himuro, and Satoshi Ito
- Subjects
Adult ,Male ,0301 basic medicine ,Fusion Proteins, bcr-abl ,Case Report ,Chromosomal translocation ,Philadelphia chromosome ,Translocation, Genetic ,Three-way variant ,03 medical and health sciences ,0302 clinical medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,t(4 ,22)(q21 ,Q34 ,Q11.2) ,medicine ,Humans ,CML ,ABL ,business.industry ,breakpoint cluster region ,Myeloid leukemia ,Karyotype ,General Medicine ,medicine.disease ,Dasatinib ,030104 developmental biology ,Karyotyping ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,business ,Bosutinib ,medicine.drug - Abstract
Background Chronic myeloid leukemia is a hematologic malignancy associated with the fusion of two genes: BCR and ABL1. This fusion results from a translocation between chromosomes 9 and 22, which is called the Philadelphia chromosome. Although the Philadelphia chromosome is present in more than 90% of patients with chronic myeloid leukemia, 5–8% of patients with chronic myeloid leukemia show complex variant translocations. Herein, we report a unique case of a three-way translocation variant in chronic phase chronic myeloid leukemia. Case presentation A 40-year-old Asian male who presented with leukocytosis was diagnosed with chronic phase chronic myeloid leukemia. Cytogenetic karyotyping analysis showed 46,XY,t(4;9;22)(q21;q34;q11.2). He was treated with bosutinib and then changed to dasatinib because of intolerance, and MR4.5 (BCR-ABL/ABL ≦ 0.0032%, international scale) was achieved after 17 months of continuous treatment. Conclusion This was the 14th case of t(4;9;22), in particular, a new variant Ph translocation involved in chromosome 4q21 and the first successful case treated with tyrosine kinase inhibitors in the world. We summarize previous case reports regarding three-way variant chromosome translocation, t(4;9;22) and discuss how this rare translocation is linked to prognosis.
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- 2021
18. 11) Leukemia Cells
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Fioretti, Tiziana, Cevenini, Armando, Zanobio, Mariateresa, Raia, Maddalena, Sarnataro, Daniela, Cattaneo, Fabio, Ammendola, Rosario, and Esposito, Gabriella
- Subjects
MLL-AF4 ,cell culture ,AF4 ,t(4 ,target therapy ,FGFR2 ,nucleus ,11) leukemia ,HOXA9 - Abstract
The chromosomal translocation t(4, 11) marks an infant acute lymphoblastic leukemia associated with dismal prognosis. This rearrangement leads to the synthesis of the MLL-AF4 chimera, which exerts its oncogenic activity by upregulating transcription of genes involved in hematopoietic differentiation. Crucial for chimera’s aberrant activity is the recruitment of the AF4/ENL/P-TEFb protein complex. Interestingly, a molecular interactor of AF4 is fibroblast growth factor receptor 2 (FGFR2). We herein analyze the role of FGFR2 in the context of leukemia using t(4, 11) leukemia cell lines. We revealed the interaction between MLL-AF4 and FGFR2 by immunoprecipitation, western blot, and immunofluorescence experiments, we also tested the effects of FGFR2 knockdown, FGFR2 inhibition, and FGFR2 stimulation on the expression of the main MLL-AF4 target genes, i.e., HOXA9 and MEIS1. Our results show that FGFR2 and MLL-AF4 interact in the nucleus of leukemia cells and that FGFR2 knockdown, which is associated with decreased expression of HOXA9 and MEIS1, impairs the binding of MLL-AF4 to the HOXA9 promoter. We also show that stimulation of leukemia cells with FGF2 increases nuclear level of FGFR2 in its phosphorylated form, as well as HOXA9 and MEIS1 expression. In contrast, preincubation with the ATP-mimetic inhibitor PD173074, before FGF2 stimulation, reduced FGFR2 nuclear amount and HOXA9 and MEIS1 transcript level, thereby indicating that MLL-AF4 aberrant activity depends on the nuclear availability of FGFR2. Overall, our study identifies FGFR2 as a new and promising therapeutic target in t(4, 11) leukemia.
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- 2021
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19. Nuclear FGFR2 Interacts with the MLL-AF4 Oncogenic Chimera and Positively Regulates HOXA9 Gene Expression in t(4;11) Leukemia Cells
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Daniela Sarnataro, Fabio Cattaneo, Gabriella Esposito, Tiziana Fioretti, Mariateresa Zanobio, Maddalena Raia, Armando Cevenini, Rosario Ammendola, Fioretti, T., Cevenini, A., Zanobio, M., Raia, M., Sarnataro, D., Cattaneo, F., Ammendola, R., and Esposito, G.
- Subjects
musculoskeletal diseases ,MLL-AF4 ,Oncogene Proteins, Fusion ,QH301-705.5 ,Chromosomal translocation ,Target therapy ,Catalysis ,Translocation, Genetic ,Inorganic Chemistry ,Chimera (genetics) ,T(4 ,Cell Line, Tumor ,hemic and lymphatic diseases ,Gene expression ,medicine ,Nucleu ,Physical and Theoretical Chemistry ,Receptor, Fibroblast Growth Factor, Type 2 ,Biology (General) ,Molecular Biology ,QD1-999 ,Spectroscopy ,Gene knockdown ,cell culture ,AF4 ,integumentary system ,Fibroblast growth factor receptor 2 ,Chemistry ,Organic Chemistry ,nucleus ,Homeodomain Protein ,General Medicine ,HOXA9 ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Computer Science Applications ,Cell biology ,Infant Acute Lymphoblastic Leukemia ,Leukemia ,Haematopoiesis ,stomatognathic diseases ,FGFR2 ,11) leukemia ,embryonic structures ,Fibroblast Growth Factor 2 ,Myeloid-Lymphoid Leukemia Protein ,Human - Abstract
The chromosomal translocation t(4;11) marks an infant acute lymphoblastic leukemia associated with dismal prognosis. This rearrangement leads to the synthesis of the MLL-AF4 chimera, which exerts its oncogenic activity by upregulating transcription of genes involved in hematopoietic differentiation. Crucial for chimera’s aberrant activity is the recruitment of the AF4/ENL/P-TEFb protein complex. Interestingly, a molecular interactor of AF4 is fibroblast growth factor receptor 2 (FGFR2). We herein analyze the role of FGFR2 in the context of leukemia using t(4;11) leukemia cell lines. We revealed the interaction between MLL-AF4 and FGFR2 by immunoprecipitation, western blot, and immunofluorescence experiments; we also tested the effects of FGFR2 knockdown, FGFR2 inhibition, and FGFR2 stimulation on the expression of the main MLL-AF4 target genes, i.e., HOXA9 and MEIS1. Our results show that FGFR2 and MLL-AF4 interact in the nucleus of leukemia cells and that FGFR2 knockdown, which is associated with decreased expression of HOXA9 and MEIS1, impairs the binding of MLL-AF4 to the HOXA9 promoter. We also show that stimulation of leukemia cells with FGF2 increases nuclear level of FGFR2 in its phosphorylated form, as well as HOXA9 and MEIS1 expression. In contrast, preincubation with the ATP-mimetic inhibitor PD173074, before FGF2 stimulation, reduced FGFR2 nuclear amount and HOXA9 and MEIS1 transcript level, thereby indicating that MLL-AF4 aberrant activity depends on the nuclear availability of FGFR2. Overall, our study identifies FGFR2 as a new and promising therapeutic target in t(4;11) leukemia.
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- 2021
20. Improved survival outcomes and relative youthfulness of multiple myeloma patients with t(4;14) receiving novel agents are associated with poorer performance of the revised international staging system in a real aging society
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Kazutaka Sunami, Akihiro Kitadate, Takeshi Yamashita, Hiroyuki Takamatsu, Mikio Ueda, Masami Takeuchi, Kentaro Narita, Yoshiaki Abe, Hiroki Kobayashi, and Kosei Matsue
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,health care facilities, manpower, and services ,Improved survival ,Aging society ,Stage ii ,03 medical and health sciences ,0302 clinical medicine ,health services administration ,Internal medicine ,medicine ,Stage (cooking) ,Staging system ,Multiple myeloma ,business.industry ,Bortezomib ,aging ,medicine.disease ,multiple myeloma ,030104 developmental biology ,Novel agents ,030220 oncology & carcinogenesis ,revised international staging system ,prognosis ,business ,t(4 ,14) ,human activities ,Research Paper ,medicine.drug - Abstract
The Revised International Staging System (R-ISS) was developed for a more accurate risk stratification of patients with symptomatic multiple myeloma (MM). However, original and subsequent validation studies of the R-ISS included relatively younger patients, many of whom were treated without bortezomib. Hence, we investigated the real-world prognostic performance of the R-ISS in 400 patients with MM treated with novel agents in Japan, an aging society. The patients had a median age of 72 years, and 96.0% were treated with bortezomib. Patients in R-ISS stage II were significantly older and failed to show significantly longer overall survival (OS) compared to patients in R-ISS stages III (median age; 74 and 70 years, respectively; P = 0.001, and median OS; 63.4 vs. 54.7 months, respectively; P = 0.32). However, OS differed significantly among patients with all conventional ISS stages. ISS stage III patients recategorized to R-ISS stage III were significantly younger than those recategorized to R-ISS stage II and had a relatively longer OS. As a reason for these findings, patients with the high-risk cytogenetic abnormality t(4;14) were significantly younger and had an improved OS compared to others, which can be attributed to a young age and bortezomib therapy, as previously suggested. In conclusion, the R-ISS was less successful than the ISS in discriminating between stages II and III among bortezomib-treated patients with MM in an aging society, which might be attributable to the inclusion of t(4;14) in the R-ISS categorization strategy.
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- 2019
21. A Case of AML Characterized by a Novel t(4;15)(q31;q22) Translocation That Confers a Growth-Stimulatory Response to Retinoid-Based Therapy
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Justin M. Watts, Aymee Perez, Lutecia Pereira, Yao-Shan Fan, Geoffrey Brown, Francisco Vega, Kevin Petrie, Ronan T. Swords, and Arthur Zelent
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acute myeloid leukemia ,t(4 ,15)(q31 ,q22) ,TMEM154-RASGRF1 ,ATRA ,retinoid ,NCT02273102 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Here we report the case of a 30-year-old woman with relapsed acute myeloid leukemia (AML) who was treated with all-trans retinoic acid (ATRA) as part of investigational therapy (NCT02273102). The patient died from rapid disease progression following eight days of continuous treatment with ATRA. Karyotype analysis and RNA-Seq revealed the presence of a novel t(4;15)(q31;q22) reciprocal translocation involving the TMEM154 and RASGRF1 genes. Analysis of primary cells from the patient revealed the expression of TMEM154-RASGRF1 mRNA and the resulting fusion protein, but no expression of the reciprocal RASGRF1-TMEM154 fusion. Consistent with the response of the patient to ATRA therapy, we observed a rapid proliferation of t(4;15) primary cells following ATRA treatment ex vivo. Preliminary characterization of the retinoid response of t(4;15) AML revealed that in stark contrast to non-t(4;15) AML, these cells proliferate in response to specific agonists of RARα and RARγ. Furthermore, we observed an increase in the levels of nuclear RARγ upon ATRA treatment. In summary, the identification of the novel t(4;15)(q31;q22) reciprocal translocation opens new avenues in the study of retinoid resistance and provides potential for a new biomarker for therapy of AML.
- Published
- 2017
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22. Nuclear FGFR2 Interacts with the MLL-AF4 Oncogenic Chimera and Positively Regulates
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Tiziana, Fioretti, Armando, Cevenini, Mariateresa, Zanobio, Maddalena, Raia, Daniela, Sarnataro, Fabio, Cattaneo, Rosario, Ammendola, and Gabriella, Esposito
- Subjects
musculoskeletal diseases ,Homeodomain Proteins ,MLL-AF4 ,cell culture ,AF4 ,integumentary system ,Oncogene Proteins, Fusion ,target therapy ,nucleus ,HOXA9 ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Translocation, Genetic ,Article ,stomatognathic diseases ,hemic and lymphatic diseases ,Cell Line, Tumor ,FGFR2 ,embryonic structures ,t(4 ,11) leukemia ,Humans ,Fibroblast Growth Factor 2 ,Receptor, Fibroblast Growth Factor, Type 2 ,Myeloid-Lymphoid Leukemia Protein - Abstract
The chromosomal translocation t(4;11) marks an infant acute lymphoblastic leukemia associated with dismal prognosis. This rearrangement leads to the synthesis of the MLL-AF4 chimera, which exerts its oncogenic activity by upregulating transcription of genes involved in hematopoietic differentiation. Crucial for chimera’s aberrant activity is the recruitment of the AF4/ENL/P-TEFb protein complex. Interestingly, a molecular interactor of AF4 is fibroblast growth factor receptor 2 (FGFR2). We herein analyze the role of FGFR2 in the context of leukemia using t(4;11) leukemia cell lines. We revealed the interaction between MLL-AF4 and FGFR2 by immunoprecipitation, western blot, and immunofluorescence experiments; we also tested the effects of FGFR2 knockdown, FGFR2 inhibition, and FGFR2 stimulation on the expression of the main MLL-AF4 target genes, i.e., HOXA9 and MEIS1. Our results show that FGFR2 and MLL-AF4 interact in the nucleus of leukemia cells and that FGFR2 knockdown, which is associated with decreased expression of HOXA9 and MEIS1, impairs the binding of MLL-AF4 to the HOXA9 promoter. We also show that stimulation of leukemia cells with FGF2 increases nuclear level of FGFR2 in its phosphorylated form, as well as HOXA9 and MEIS1 expression. In contrast, preincubation with the ATP-mimetic inhibitor PD173074, before FGF2 stimulation, reduced FGFR2 nuclear amount and HOXA9 and MEIS1 transcript level, thereby indicating that MLL-AF4 aberrant activity depends on the nuclear availability of FGFR2. Overall, our study identifies FGFR2 as a new and promising therapeutic target in t(4;11) leukemia.
- Published
- 2021
23. Frequency of t(4;14) in Multiple Myeloma and Its Clinicopathological Correlation.
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Zaheer, Saima, Robert, Helen Mary, Mahmood, Asad, Mahmood, Rafia, Khurshid, Ayesha, and Khan, Nabeela
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- *
MULTIPLE myeloma , *PAKISTANIS , *CONVENIENCE sampling (Statistics) , *FLUORESCENCE in situ hybridization , *IMMUNOGLOBULIN heavy chains - Abstract
Objective: To determine the frequency of t(4;14) in multiple myeloma in Pakistani population and study the clinicpathological correlation of this translocation in myeloma patients. Study Design: Cross sectional study. Place and Duration of Study: This study was conducted at Armed Forces Institute of Pathology from Jun 2017 to May 2018 using non probability convenience sampling technique. Methodology: A total of 53 newly diagnosed cases of multiple myeloma were included in the study. Patients were diagnosed as having multiple myeloma based on diagnostic criteria of international myeloma working group. Fish analysis was done for t (4; 14). Workup for end organ damage/myeloma defining events was done. Results: Out of 53 patients, 16 (30%) were females and 37(70%) were males; the mean age of the patients was 59.81 ± 11.34 range from 37 to 87 years. Fish for t(4;14) was positive in eight (15%) patients while negative in forty-five (85%) patients. Patients with positive results have significantly deranged renal function tests and raised beta 2 micoglobulins levels as compare to t(4;14)negative patients. Conclusions: Detection of t (4:14) in multiple myeloma patients not only has diagnostic value but is important in risk stratification of these patients and thus effect treatment decision. [ABSTRACT FROM AUTHOR]
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- 2022
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24. Targeting
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Parin, Kamseng, Teerapong, Siriboonpiputtana, Teeraya, Puavilai, Suporn, Chuncharunee, Karan, Paisooksantivatana, Takol, Chareonsirisuthigul, Mutita, Junking, Wannasiri, Chiraphapphaiboon, Pa-Thai, Yenchitsomanus, and Budsaba, Rerkamnuaychoke
- Subjects
Aged, 80 and over ,Chromosomes, Human, Pair 14 ,Male ,Cell Cycle Checkpoints ,Middle Aged ,t(4 ,14) multiple myeloma ,UCHL1 ,Translocation, Genetic ,Gene Expression Regulation, Neoplastic ,expression profile ,Society Journal Archive ,Humans ,biomarker ,Female ,Chromosomes, Human, Pair 4 ,Multiple Myeloma ,Transcriptome ,Ubiquitin Thiolesterase ,cell cycle regulation ,Aged ,Original Research - Abstract
Multiple myeloma (MM) patients considered to be at high cytogenetic risk commonly fail to respond to standard treatment. A thorough understanding of the molecular mechanism of MM development is, therefore, needed. We endeavored to explore the transcriptional signature among different subgroups of newly diagnosed MM using gene chip-based expression microarray. Bone marrow samples of 15 newly diagnosed Thai MM patients were included. The chromosomal translocation t(4;14) was the most frequently identified genetic alteration in the high-risk subgroup. Cluster analysis from expression profiling demonstrated that high-risk MM have a distinctly different expression pattern compared to standard-risk patients. The most significant differentially expressed gene was UCHL1. Functional enrichment analysis by Gene Set Enrichment Analysis, FUNRICH, and Gene Ontology Panther pathway revealed the gene sets involved in cell cycle control to be enriched in the t(4;14) high-risk group. Interestingly, among the well-established downstream targets of UCHL1, only CCND2 was significantly expressed in the t(4;14) high-risk group. Suppression of UCHL1 protein level by LDN-5744 inhibitor could arrest the cell cycle in G1 phase in cell lines. These findings shed light on the molecular mechanism of UCHL1 in t(4;14) high-risk MM and support the evidence that alteration of the UCHL1 pathway may play a role in the pathogenesis of high-risk MM.
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- 2020
25. B-cell acute lymphoblastic leukemia with t(4;11)(q21;q23) in a young woman: evolution into mixed phenotype acute leukemia with additional chromosomal aberrations in the course of therapy
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Giovanni Carulli, Alessandra Marini, Maria I. Ferreri, Antonio Azzarà, Virginia Ottaviano, Tiziana Lari, Melania Rocco, Stefano Giuntini, and Mario Petrini
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acute lymphoblastic leukemia ,acute myeloid leukemia ,mixed phenotype acute leukemia ,MLL gene ,t(4 ,11)(q21 ,q23) ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
About 5% of adult B-cell acute lymphoblastic leukemias (B-ALL) are characterized by t(4;11)(q21;q23), which confers peculiar features to this B-ALL subtype, including a very immature immunophenotype and poor prognosis. We describe the case of a 21-year-old female who presented with B-ALL carrying the t(4;11)(q21;q23) and blasts positive for CD19, TdT, CD79a, CD38, HLA-DR. Before completing the Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) therapy regimen, the B-cell leukemic clone still was detected, but an additional leukemic clone appeared, with morphology and immunophenotype (CD13, CD33, CD64, CD38, CD56, CD15, CD4dim) compatible with derivation from the myeloid/monocytic lineage. Karyotype showed the co-existence of three cell lines, with persistence of t(4;11)(q21;q23) and appearance of +8,+12,+13 and two der(4). The patient died because of disseminated intravas- cular coagulation. Our report describes a rare, possible evolution of such a subtype of B-ALL, with transformation into mixed phenotype acute leukemia in the course of therapy. This finding suggests a blast cell derivation from a common lymphoid/monocytic precursor leading to a final bilineal acute leukemia.
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- 2012
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26. Acute myeloid leukemia with t(4;12)(q12;p13): an aggressive disease with frequent involvement of PDGFRA and ETV6
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Elias Jabbour, Jingyi Li, L. Jeffrey Medeiros, Gary Lu, Lynne V. Abruzzo, C. Cameron Yin, Jie Xu, Shaoying Li, Qi Deng, Carlos E. Bueso-Ramos, Guilin Tang, and M. James You
- Subjects
medicine.medical_specialty ,NPM1 ,Myeloid ,CD33 ,PDGFRA ,acute myeloid leukemia ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,hemic and lymphatic diseases ,CEBPA ,t(4 ,12)(q12 ,p13) ,Medicine ,biology ,business.industry ,CD117 ,Myeloid leukemia ,Correction ,ETV6 ,Transplantation ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,business ,030215 immunology ,Research Paper - Abstract
We describe the clinical, morphologic, immunophenotypic and molecular genetic features of 15 cases of acute myeloid leukemia (AML) with t(4;12)(q12;p13). There were 9 men and 6 women, with a median age of 50 years (range, 17-76). Most patients had hypercellular bone marrow with a median blast count of 58% and multilineage dysplasia. Flow cytometry analysis showed myeloid lineage with blasts positive for CD13, CD33, CD34, CD38, CD117 and HLA-DR. Interestingly, aberrant CD7 expression was detected in 12/14 cases, and myeloperoxidase was either negative (3/15) or positive in only a small subset of the blasts (12/15). t(4;12)(q12;p13) was detected at time of initial diagnosis in 4 and at relapse or progression in 9 patients. The initial karyotype was unknown in 2 cases. FISH analysis showed PDGFRA-ETV6 rearrangement in all 7 cases assessed. FLT3 ITD was detected in 2/11 cases and IDH2 and JAK2 mutation were each detected in 1/2 cases assessed. There were no mutations of KRAS (0/8), NRAS (0/8), CEBPA (0/3), KIT (0/3), NPM1 (0/3) or IDH1 (0/2). All patients received aggressive multiagent chemotherapy; 7 patients additionally received stem cell transplantation. With a median follow-up of 10 months (range, 6-51), 13 patients died of AML, 1 patient had persistent disease, and 1 patient was lost to follow-up. In summary, AML with t(4;12)(q12;p13) is usually associated with myelodysplasia, aberrant CD7 expression, weak of absent myeloperoxidase expression, frequent PDGFRA-ETV6 fusion, and an aggressive clinical course. The molecular findings suggest that there may be a role for tyrosine kinase inhibitors in patient management.
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- 2017
27. t(4;22)(q12;q11.2) involving presumptive platelet-derived growth factor receptor A and break cluster region in a patient with mixed phenotype acute leukemia.
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Wang, Huan-You, Thorson, John A., Broome, H. Elizabeth, Rashidi, Hooman H., Curtin, Peter T., and Dell'Aquila, Marie L.
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ACUTE leukemia ,GROWTH factors ,BREAST cancer ,CYTOMETRY ,CANCER cells ,FLUORESCENCE in situ hybridization ,PROTEIN-tyrosine kinase inhibitors ,PATIENTS - Abstract
Summary: The patient is a 45-year-old woman with a history of breast cancer who had been treated 1 year ago with radiation and chemotherapy. Flow cytometric analysis of bone marrow aspirate revealed 81% blasts positive for CD4, CD11c (partial), CD13, CD19 (partial), cytoplasmic CD22, CD34, CD36, CD45, cytoplasmic CD79a, CD117 (partial), HLA-DR, and terminal deoxynucleotide transferase, consistent with a mixed phenotype acute leukemia (B/myeloid lineage). Conventional karyotypic analysis revealed a t(4;22)(q12;q11.2) in 12 of 13 cells analyzed. Fluorescence in situ hybridization analysis using a dual-color, dual-fusion break cluster region/ABL probe set showed no break cluster region/ABL translocation but an extra break cluster region signal in 85% (170/200) of cells, consistent with a translocation involving the break cluster region gene at 22q11.2. A FIP1L1/CHIC2/platelet-derived growth factor receptor α deletion/fusion probe showed signal separation in 96.5% (193/200) of interphase nuclei. Reverse transcriptase–polymerase chain reaction using sense break cluster region primers and an antisense platelet-derived growth factor receptor α primer resulted in a product of approximately 590 base pairs, consistent with the presence of a break cluster region/platelet-derived growth factor receptor α fusion gene. Because of the presumptive platelet-derived growth factor receptor α translocation and its sensitivity to tyrosine-kinase inhibitor, the patient was treated with imatinib mesylate, cytarabine, and idarubicin as induction and maintenance therapy; and she has remained free of disease for 5 months since the initial diagnosis. [ABSTRACT FROM AUTHOR]
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- 2011
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28. t(4;11) leukemias display addiction to MLL-AF4 but not to AF4-MLL
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Kumar, Ashish R., Yao, Qing, Li, Quanzhi, Sam, Thien A., and Kersey, John H.
- Subjects
- *
CHROMOSOMAL translocation , *LEUKEMIA , *CHROMOSOMES , *APOPTOSIS , *CELL cycle , *CELL proliferation , *CELL lines - Abstract
Abstract: The most frequent MLL-gene rearrangement found in leukemia is a reciprocal translocation with AF4 on chromosome 4 resulting in the formation of the MLL-AF4 and the AF4-MLL fusion genes. The oncogenic role of MLL-AF4 is documented but the significance of the reciprocal product – AF4-MLL in leukemia is less clear. In the human leukemia cell lines – RS4;11 and SEMK2-M1, both of which express MLL-AF4 and AF4-MLL, we knocked down the expression of AF4-MLL using siRNA. Loss of AF4-MLL had no effect on the growth of either RS4;11 or SEMK2-M1 cells. Furthermore, in SEMK2-M1 cells there were no changes in cell cycle or apoptosis with loss of AF4-MLL. In contrast, knockdown of MLL-AF4 significantly inhibited growth of both RS4;11 and SEMK2-M1. Additionally, in SEMK2-M1 cells, loss of MLL-AF4 led to G2/M cell cycle arrest and increased apoptosis. Overall, these results demonstrate that in t(4;11) leukemia, the MLL-AF4 fusion protein is critical for leukemia cell proliferation and survival while the AF4-MLL fusion product is dispensable. [Copyright &y& Elsevier]
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- 2011
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29. Limited survivability of unbalanced progeny of carriers of a unique t(4;19)(p15.32;p13.3): a study in multiple generations
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Bernarda Lozić, Zeljka Bilinovac, Beata Stasiewicz-Jarocka, Tatijana Zemunik, Barbara Panasiuk, Darinka Šumanović-Glamuzina, Alina T. Midro, and Piotr S. Iwanowski
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0301 basic medicine ,medicine.medical_specialty ,Monosomy ,Estimation of recurrence probability ,lcsh:QH426-470 ,Morphological phenotype ,Genetic counseling ,Miscarriages ,Chromosomal translocation ,030105 genetics & heredity ,Biology ,Biochemistry ,Miscarriage ,03 medical and health sciences ,Trisomy 19p13.3 → pter ,Genetics ,medicine ,Molecular Biology ,Wolf–Hirschhorn syndrome ,t(4 ,19)(p15.32 ,p13.3) ,Genetics (clinical) ,Wolf-Hirschhorn syndrome ,Obstetrics ,Research ,Biochemistry (medical) ,Cytogenetics ,Stillbirth ,medicine.disease ,Human genetics ,Monosomy 4p15.32 → pter ,lcsh:Genetics ,Molecular Medicine ,Trisomy - Abstract
Background Carriership of a reciprocal chromosomal translocation (RCT) involving the short arm of chromosome 4 (4p) may result in birth of a child with Wolf-Hirschhorn syndrome (WHS) due to monosomy 4p, a priori modified by the impact of the partner chromosome imbalance. Familial transmission studies of RCT enable obtaining empirical risk figures that are essential for genetic counseling. In this study, pedigree data from carriers of a unique t(4;19)(p15.32;p13.3), ascertained by two children with WHS phenotype, were collected through five generations and empirical risk for different pregnancy outcomes was assessed. In addition, the phenotype-karyotype correlation was studied in two unbalanced children against the phenotypes of children (literature data) with pure monosomy 4p15.32 → pter and pure trisomy 19p13.3 → pter, accordingly. The phenotype analysis was conducted using the catalogue of traits according to the Munich Dysmorphology Database. Pedigree segregation analysis was conducted by the direct method according to Stengel- Rutkowski et al. Results A double segment imbalance, trisomy 19p13.3 → pter with monosomy 4p15.32 → pter, was diagnosed in WHS progeny at birth. No essential modification of WHS phenotype by the additional trisomy 19p was observed, except for a limited survivability (death in infancy). Pedigree segregation analysis covered 39 relatives showed the probability rate for liveborn with unbalanced karyotype of 3.7 ± 3.6% (1/27), for stillbirth/neonatal death at 7.4 ± 5.0% (2/27), for miscarriage at 22.2 ± 8.0% (6/27), for the chance of having a baby without unbalanced karyotype was estimated at 66.7 ± 9.1% (18/27). In addition, the value of 7.4% for genetic counseling for any carrier of RCT at risk for single segment 19p13.3 → pter imbalance at birth was evaluated as such value have not been estimated so far. Conclusion Carriership of a t(4;19)(p15.32;p13.3) is at low risk for an unbalanced child at birth and for stillbirth/neonatal death but high for miscarriages. The chance of having a baby without unbalanced karyotype was estimated to be high. Monosomy 4p15.32 → pter together with trisomy 19p13.3 → pter as a double segment imbalance in children with WHS may be connected with a limited survivability in infancy. Electronic supplementary material The online version of this article (doi:10.1186/s13039-017-0330-8) contains supplementary material, which is available to authorized users.
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- 2017
30. Acute lymphoblastic leukemia with 4;11 translocation analyzed by a multi-modal strategy of conventional cytogenetics, FISH, morphology, flow cytometry and molecular genetics, and review of the literature
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Hayne, Cynthia C., Winer, Eric, Williams, Tara, Chaves, Fernando, Khorsand, Jila, and Mark, Hon Fong L.
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CHROMOSOMES , *MOLECULAR biology , *MOLECULAR genetics , *LYMPHOCYTIC leukemia - Abstract
Abstract: We report a case of acute lymphoblastic leukemia (ALL) with a 4;11 translocation. Metaphase cells and interphase nuclei derived from a routine unstimulated culture of bone marrow were analyzed using a combined strategy of G-banding and fluorescent in situ hybridization (FISH) in addition to hematopathological analysis, flow cytometry, and molecular genetics. This multimodal approach enables a successful correlation of pathology and cytogenetics to support a comprehensive diagnosis of the patient. Meaningful prognostication and appropriate therapeutic considerations are possible only when accurate diagnostic information is given. We further search and review the literature for the most up-to-date information currently available for this subtype of ALL in the constantly evolving field of molecular cytogenetics. [Copyright &y& Elsevier]
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- 2006
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31. MB4-2/MB4-3 transcripts of IGH-MMSET fusion gene in t(4;14)pos multiple myeloma indicate poor prognosis
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Yu-Mei Tang, Qian Zhao, Hui Zhang, Ting Lai, Jian Hou, Feng Li, and Yongping Zhai
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Prognostic variable ,Fusion gene ,03 medical and health sciences ,major breakpoint (MB4) ,Internal medicine ,medicine ,Clinical significance ,Stage (cooking) ,MMSET gene ,Multiple myeloma ,Bortezomib ,business.industry ,t(4 ,14) translocation ,bortezomib ,Breakpoint ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,prognosis ,Bone marrow ,business ,Research Paper ,medicine.drug - Abstract
Multiple myeloma (MM) patients with t(4;14) is a heterogeneous group. Prognostic tools capable of predicting the outcome of patients are currently lacking. The MM SET domain (MMSET) protein is universally overexpressed and has been suggested to have an important tumorigenic role. This study analyzed whether the overexpression of full-length (MB4-1) or truncated forms (MB4-2 and MB4-3) of MMSET influence the prognosis of t(4;14)pos MM patients. A total of 53 symptomatic t(4;14)pos MM patients were retrospectively analyzed. RT-PCR was performed using cDNA from purified CD138+ bone marrow plasma cells to analyze expression and clinical significance of the IGH-MMSET fusion transcripts corresponding to MB4-1, MB4-2 and MB4-3 breakpoints. Among the patients, 25 (47.2%), 12 (22.6%) and 16 (30.2%) had the MB4-1, MB4-2 and MB4-3 breakpoints, respectively. When adjusted to the established prognostic variables including del(17p), ISS stage, serum LDH and serum calcium levels, the pooled MB4-2/MB4-3 subgroup remained a powerful independent adverse factor for PFS (P=0.013) and OS (P=0.029). Bortezomib-based therapy significantly improved the survival of the MB4-1 subgroup but could not overcome the negative effect of the MB4-2/MB4-3 breakpoints. Our results indicate that MB4-2/MB4-3 breakpoints with truncated forms of MMSET define a subset of t(4;14)posMM with poor prognosis.
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- 2017
32. Acute Lymphoblastic Leukemia with t(4; 11)(q21; q23)/KMT2A-AFF1 Translocation: The Results of Allogeneic Hematopoietic Stem Cells Transplantation in Children and Adults
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AS Borovkova, NN Mamaev, TL Gindina, Elena I. Darskaya, Sergey N. Bondarenko, YaV Gudozhnikova, L.S. Zubarovskaya, OA Slesarchuk, BV Afanas’ev, O.V. Paina, P.V. Kozhokar, and AL Alyanskii
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biology ,business.industry ,Lymphoblastic Leukemia ,allogeneic HSCT ,Chromosomal translocation ,acute lymphoblastic leukemia ,t(4 ,11)/KMT2A-AFF1 translocation ,Hematology ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Transplantation ,Haematopoiesis ,KMT2A ,Oncology ,Cancer research ,biology.protein ,Medicine ,Stem cell ,business - Abstract
Aim. The aim was to evaluate the results of the allogeneic hematopoietic stem cells transplantation (allo-HSCT) in children and adults with the most prognostically unfavorable acute lymphoblastic leukemia (ALL) with t(4; 11)(q21; q23)/KMT2A-AFF1 translocation. Methods. We examined 21 patients (12 females, 9 males) aged from 3 months to 48 years (median 18.9 years). The analysis of prognostic factors of overall (OS) and eventfree survival (EFS) after allo-HSCT in patients of different age groups with various clinical, transplantation and cytogenetic characteristics was performed. Allo-HSCT from HLA-compatible related and unrelated donors, as well as haploidentical allo-HSCT were performed in 4, 9 and 8 patients of age groups < 1 year, 1-18 years, and >18 years, respectively. In 10 (48 %) patients, allo-HSCT was performed in the first remission, in 2 (10 %) patients in the second remission, and in 9 (43 %) patients during the disease relapse. Results. In 8 (38 %) patients, the only chromosomal disorder was the translocation t(4; 11)(q21; q23). Additional changes in chromosomes were found in 11 (52 %) patients. In 8 (38 %) of them, 3 or more chromosomal abnormalities in the karyotype were found. According to the results of a univariant analysis, the OS and EFS were significantly different in patients with allo-HSCT performed in the first remission and at other stages of ALL (in the second remission and in relapse: p < 0.001 in both cases), as well as in patients with or without 3 or more cytogenetic disorders in the karyotype (p = 0.04 in both cases). The multivariant analysis showed that the only independent prognostic factor affecting the OS and EFS in ALL patients with t(4; 11) was the allo-HSCT, including the haploidentical procedure, during the first complete hematological and molecular remission (p = 0.002 and p = 0.0004, respectively). Conclusion. ALL with t(4; 11)/KMT2A-AFF1 was as an absolute indication for allo-HSCT in first remission, including children of < 1 year age group. Satisfactory results can be obtained with the use of haploidentical transplantation from the parents. This approach eliminates the search in the registers completely HLA-compatible donor and facilitates the treatment procedure.
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- 2017
33. Ponte di Legno Working Group: statement on the right of children with leukemia to have full access to essential treatment and report on the Sixth International Childhood Acute Lymphoblastic Leukemia Workshop.
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Pui, C.-H., Schrappe, M., Masera, G., Nachman, J., Gadner, H., Eden, O. B., Evans, W. E., and Gaynon, P.
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LEUKEMIA , *CANCER , *CHILDREN'S rights , *CHARITIES , *CHILDREN'S health , *CANCER research - Abstract
The Sixth International Childhood ALL Workshop was made possible by unrestricted educational grants from Sanofi-Synethelabo Inc., Glaxosmithkline, Enzon Inc., and Ilex. Preparation of the Meeting Report was supported in part by the Österreichische Kinderkrebshilfe and private donations to the Children's Cancer Research Institute; the Associazione Italiana Ricerca sul Cancro, Fondazione Tettamanti, and Consiglio Nazionale Ricerche-Ministero Instruzione Universitá Ricerca); the Deutsche Krebshilfe, Bonn, and Madeleine Schickedanz Foundation, Fürth, Germany; Cancer Research UKJ; grants from the US National Institutes of Health (CA-21765, CA-51001, CA-31566, CA-78824, CA-29139, CA-37379, GM-61393, and GM61374), a Center of Excellence grant from the State of Tennessee, and the American Lebanese Syrian Associated Charities (ALSAC). C-H Pui is the American Cancer Society - FM Kirby Clinical Research Professor.Leukemia (2004) 18, 1043-1053. doi:10.1038/sj.leu.2403365 Published online 15 April 2004 [ABSTRACT FROM AUTHOR]
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- 2004
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34. Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074.
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Grand, E. K., Chase, A. J., Heath, C., Rahemtulla, A., and Cross, N. C. P.
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MULTIPLE myeloma , *PATIENTS , *THERAPEUTICS , *DOSAGE forms of drugs , *APOPTOSIS , *GENE expression - Abstract
The t(4;14)(p16.3;q32), associated with 10–20% of cases of multiple myeloma (MM), deregulates the expression of MMSET and FGFR3. To assess the potential of FGFR3 as a drug target, we evaluated the effects of selective inhibitors on MM and control cell lines. SU5402 and PD173074 specifically inhibited the growth of the two t(4;14)-positive MM lines, KMS-11 and OPM-2. Importantly, inhibition was still observed in the presence of IL-6, a growth factor known to play an important role in MM. Both compounds induced a dose-dependent reduction in cell viability and an increase in apoptosis, accompanied by a decrease in extracellular signal-related kinase phosphorylation. In contrast, no inhibition was seen with either compound against t(4;14)-negative cell lines or NCI-H929, a t(4;14)-positive, FGFR3-negative MM cell line. FGFR3 is thus a plausible candidate for targeted therapy in a subset of MM patients. [ABSTRACT FROM AUTHOR]
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- 2004
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35. t(4;12)(q11;p13): a rare chromosomal translocation in acute myeloid leukemia
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Chauffaille, Maria de Lourdes L.F., Fermino, Fabiana A., Pelloso, Luis A.F., Silva, Maria R.R., Bordin, José O., and Yamamoto, Mihoko
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- *
ACUTE myeloid leukemia , *DYSPLASIA - Abstract
We present a case of acute myeloid leukemia with t(4;12). This translocation is rare and has been observed in acute leukemias with different but immature phenotypes. To the best of our knowledge, there are around 15 descriptions of t(4;12) in AML, and most interesting, presenting morphological aspects of a pseudo-lymphoid cell with dysplasia of other series. [Copyright &y& Elsevier]
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- 2003
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36. A variant of acute promyelocytic leukemia with t(4;17)(q12;q21) showed two different clinical symptoms
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Ryo Saito, Koji Tsuta, Yoshiko Azuma, Masaaki Hotta, Yoshihiko Kadosaka, Hideaki Yoshimura, Yusuke Nishio, Atsushi Satake, Shosaku Nomura, Yukie Tsubokura, Shinya Fujita, Akiko Konishi, Takahisa Nakanishi, Kazuyoshi Ishii, Aya Nakaya, and Tomoki Ito
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Acute promyelocytic leukemia ,Retinoic acid ,Salvage therapy ,Case Report ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,Myeloblast ,hemic and lymphatic diseases ,Medicine ,PML-RARA ,neoplasms ,t(4 ,17)(q12 ,q21) ,business.industry ,lcsh:RC633-647.5 ,Myeloid leukemia ,Induction chemotherapy ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,acute promyelocytic leukemia ,medicine.disease ,all-trans retinoic acid ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,business ,030215 immunology - Abstract
A 63-year-old man was diagnosed with a rare variant of acute promyelocytic leukemia (APL) with t(4;17)(q12; q21) that showed atypical morphological features and two different clinical symptoms. He was started on standard induction chemotherapy for acute myeloid leukemia, which decreased myeloblast numbers; however, APL-like blasts remained. He then received a salvage therapy that added all-trans retinoic acid (ATRA). After ATRA commenced, APL-like blasts disappeared and cytogenetic analysis became normal. However, myeloblasts subsequently increased, and he became resistant. In summary, this patient exhibited two different clinical courses of acute myeloid leukemia and APL.
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- 2019
37. The RS4;11 cell line as a model for leukaemia with t(4;11)(q21;q23): Revised characterisation of cytogenetic features
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Catherine M. Green, Silvano Tosi, Daniela Moralli, Evgeny M. Makarov, Oliver Britten, and Denise Ragusa
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MLL ,Cancer Research ,medicine.medical_specialty ,Oncogene Proteins, Fusion ,clonal evolution ,Chromosomal translocation ,Biology ,t(4 ,11)(q23 ,q21) ,Translocation, Genetic ,Fusion gene ,Molecular cytogenetics ,Cytogenetics ,Cell Line, Tumor ,Gene duplication ,medicine ,Humans ,Cancer genetics ,Sequence Deletion ,RS4 ,Genetics ,Leukemia ,Chromosomes, Human, Pair 11 ,Hematological cancer ,Chromosome ,Karyotype ,Histone-Lysine N-Methyltransferase ,Original Articles ,KMT2A ,DNA-Binding Proteins ,Oncology ,Fusion transcript ,Karyotyping ,leukaemia ,Original Article ,Chromosomes, Human, Pair 4 ,Transcriptional Elongation Factors ,Myeloid-Lymphoid Leukemia Protein - Abstract
Background Haematological malignancies harbouring rearrangements of the KMT2A gene represent a unique subtype of leukaemia, with biphenotypic clinical manifestations, a rapid and aggressive onset, and a generally poor prognosis. Chromosomal translocations involving KMT2A often cause the formation of oncogenic fusion genes, such as the most common translocation t(4;11)(q21;q23) producing the KMT2A‐AFF1 chimera. Aim The aim of this study was to confirm and review the cytogenetic and molecular features of the KMT2A‐rearranged RS4;11 cell line and put those in context with other reports of cell lines also harbouring a t(4;11) rearrangement. Methods and Results The main chromosomal rearrangements t(4;11)(q21;q23) and i(7q), described when the cell line was first established, were confirmed by fluorescence in situ hybridisation (FISH) and 24‐colour karyotyping by M‐FISH. Additional cytogenetic abnormalities were investigated by further FISH experiments, including the presence of trisomy 18 as a clonal abnormality and the discovery of one chromosome 8 being an i(8q), which indicates a duplication of the oncogene MYC. A homozygous deletion of 9p21 containing the tumour‐suppressor genes CDKN2A and CDKN2B was also revealed by FISH. The production of the fusion transcript KMT2A‐AFF1 arising from the der(11)t(4;11) was confirmed by RT‐PCR, but sequencing of the amplified fragment revealed the presence of multiple isoforms. Two transcript variants, resulting from alternative splicing, were identified differing in one glutamine residue in the translated protein. Conclusion As karyotype evolution is a common issue in cell lines, we highlight the need to monitor cell lines in order to re‐confirm their characteristics over time. We also reviewed the literature to provide a comparison of key features of several cell lines harbouring a t(4;11). This would guide scientists in selecting the most suitable research model for this particular type of KMT2A‐leukaemia.
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- 2019
38. Crosstalk between 14-3-3θ and AF4 enhances MLL-AF4 activity and promotes leukemia cell proliferation
- Author
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Maddalena Raia, Gabriella Esposito, Tiziana Fioretti, Francesco Salvatore, Mariateresa Zanobio, Armando Cevenini, Daniela Sarnataro, Fioretti, T., Cevenini, A., Zanobio, Mariateresa, Raia, M., Sarnataro, D., Salvatore, F., and Esposito, G.
- Subjects
0301 basic medicine ,MLL ,Cancer Research ,Oncogene Proteins, Fusion ,Transcription, Genetic ,11) ,Apoptosis ,Translocation, Genetic ,Fusion gene ,0302 clinical medicine ,hemic and lymphatic diseases ,Gene expression ,Serine ,Protein partner ,Myeloid Ecotropic Viral Integration Site 1 Protein ,Promoter Regions, Genetic ,Gene knockdown ,AF4 ,Leukemia ,Gene Expression Regulation, Leukemic ,Chemistry ,General Medicine ,HOXA9 ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,KMT2A ,Chromatin ,Cell biology ,DNA-Binding Proteins ,Oncology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Transcriptional Elongation Factors ,Myeloid-Lymphoid Leukemia Protein ,Protein Binding ,DNA, Complementary ,Cell Survival ,Immunoprecipitation ,Models, Biological ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Humans ,Protein Interaction Domains and Motifs ,Transcription factor ,Cell Proliferation ,Cell Nucleus ,Homeodomain Proteins ,medicine.disease ,HEK293 Cells ,030104 developmental biology ,t(4 ,14-3-3 Proteins ,Chromatin immunoprecipitation - Abstract
The t(4;11)(q21;q23) translocation characterizes a form of acute lymphoblastic leukemia with a poor prognosis. It results in a fusion gene encoding a chimeric transcription factor, MLL-AF4, that deregulates gene expression through a variety of still controversial mechanisms. To provide new insights into these mechanisms, we examined the interaction between AF4, the most common MLL fusion partner, and the scaffold protein 14-3-3θ, in the context of t(4;11)-positive leukemia. Protein-protein interactions were analyzed using immunoprecipitation and in vitro binding assays, and by fluorescence microscopy in t(4;11)-positive RS4;11 and MV4–11 leukemia cells and in HEK293 cells. Protein and mRNA expression levels were determined by Western blotting and RT-qPCR, respectively. A 5-bromo-2′-deoxyuridine assay and an annexin V/propidium iodide assay were used to assess proliferation and apoptosis rates, respectively, in t(4;11)-positive and control cells. Chromatin immunoprecipitation was performed to assess binding of 14-3-3θ and AF4 to a specific promoter element. We found that AF4 and 14-3-3θ are nuclear interactors, that 14-3-3θ binds Ser588 of AF4 and that 14-3-3θ forms a complex with MLL-AF4. In addition, we found that in t(4;11)-positive cells, 14-3-3θ knockdown decreased the expression of MLL-AF4 target genes, induced apoptosis and hampered cell proliferation. Moreover, we found that 14-3-3θ knockdown impaired the recruitment of AF4, but not of MLL-AF4, to target chromatin. Overall, our data indicate that the activity of the chimeric transcription factor MLL-AF4 depends on the cellular availability of 14-3-3θ, which triggers the transactivating function and subsequent degradation of AF4. From our data we conclude that the scaffold protein 14-3-3θ enhances the aberrant activity of the chimeric transcription factor MLL-AF4 and, therefore, represents a new player in the molecular pathogenesis of t(4;11)-positive leukemia and a new promising therapeutic target.
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- 2019
39. Case of Patient with AML with Complex Karyotype including Ultra-Rare t(4;8)(q32;q13), t(4;11)(q21;p15) and Familial Aggregation of Myeloid Malignancies.
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Milczarek S, Studniak E, Baumert B, Janowski M, Bonda W, Pietrzak J, Łanocha A, Paczkowska E, Zdziarska B, and Machaliński B
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- Female, Humans, Karyotype, Pedigree, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Translocation, Genetic
- Abstract
We present a unique case of a young woman with acute myeloid leukemia (AML) with complex karyotype. The presence of the t(4;11)(q23;p15) is extremely rare in myeloid leukemias, while t(4;8)(q32;q13) has not yet been described in any leukemia reference. Another interesting issue is the familial aggregation of myeloid malignancies and worse course of the disease in each subsequent generation, as well as an earlier onset of the disease. Our report emphasizes the need for thorough pedigree examination upon myeloid malignancy diagnosis as there are relatives for whom counseling, gene testing, and surveillance may be highly advisable.
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- 2022
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40. A recurrent translocation is mediated by homologous recombination between HERV-H elements
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Hermetz Karen E, Surti Urvashi, Cody Jannine D, and Rudd M Katharine
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HERV-H ,HERV ,NAHR ,translocation ,t(4 ,18) ,recurrent translocation ,4q35.1 ,18q22.3 ,18q ,Genetics ,QH426-470 - Abstract
Abstract Background Chromosome rearrangements are caused by many mutational mechanisms; of these, recurrent rearrangements can be particularly informative for teasing apart DNA sequence-specific factors. Some recurrent translocations are mediated by homologous recombination between large blocks of segmental duplications on different chromosomes. Here we describe a recurrent unbalanced translocation casued by recombination between shorter homologous regions on chromosomes 4 and 18 in two unrelated children with intellectual disability. Results Array CGH resolved the breakpoints of the 6.97-Megabase (Mb) loss of 18q and the 7.30-Mb gain of 4q. Sequencing across the translocation breakpoints revealed that both translocations occurred between 92%-identical human endogenous retrovirus (HERV) elements in the same orientation on chromosomes 4 and 18. In addition, we find sequence variation in the chromosome 4 HERV that makes one allele more like the chromosome 18 HERV. Conclusions Homologous recombination between HERVs on the same chromosome is known to cause chromosome deletions, but this is the first report of interchromosomal HERV-HERV recombination leading to a translocation. It is possible that normal sequence variation in substrates of non-allelic homologous recombination (NAHR) affects the alignment of recombining segments and influences the propensity to chromosome rearrangement.
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- 2012
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41. Nuclear FGFR2 Interacts with the MLL-AF4 Oncogenic Chimera and Positively Regulates HOXA9 Gene Expression in t(4;11) Leukemia Cells.
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Fioretti T, Cevenini A, Zanobio M, Raia M, Sarnataro D, Cattaneo F, Ammendola R, and Esposito G
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- Cell Line, Tumor, Fibroblast Growth Factor 2, Humans, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Translocation, Genetic, Homeodomain Proteins metabolism, Myeloid-Lymphoid Leukemia Protein metabolism, Oncogene Proteins, Fusion metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Receptor, Fibroblast Growth Factor, Type 2 metabolism
- Abstract
The chromosomal translocation t(4;11) marks an infant acute lymphoblastic leukemia associated with dismal prognosis. This rearrangement leads to the synthesis of the MLL-AF4 chimera, which exerts its oncogenic activity by upregulating transcription of genes involved in hematopoietic differentiation. Crucial for chimera's aberrant activity is the recruitment of the AF4/ENL/P-TEFb protein complex. Interestingly, a molecular interactor of AF4 is fibroblast growth factor receptor 2 (FGFR2). We herein analyze the role of FGFR2 in the context of leukemia using t(4;11) leukemia cell lines. We revealed the interaction between MLL-AF4 and FGFR2 by immunoprecipitation, western blot, and immunofluorescence experiments; we also tested the effects of FGFR2 knockdown, FGFR2 inhibition, and FGFR2 stimulation on the expression of the main MLL-AF4 target genes, i.e., HOXA9 and MEIS1 . Our results show that FGFR2 and MLL-AF4 interact in the nucleus of leukemia cells and that FGFR2 knockdown, which is associated with decreased expression of HOXA9 and MEIS1 , impairs the binding of MLL-AF4 to the HOXA9 promoter. We also show that stimulation of leukemia cells with FGF2 increases nuclear level of FGFR2 in its phosphorylated form, as well as HOXA9 and MEIS1 expression. In contrast, preincubation with the ATP-mimetic inhibitor PD173074, before FGF2 stimulation, reduced FGFR2 nuclear amount and HOXA9 and MEIS1 transcript level, thereby indicating that MLL-AF4 aberrant activity depends on the nuclear availability of FGFR2. Overall, our study identifies FGFR2 as a new and promising therapeutic target in t(4;11) leukemia.
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- 2021
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42. Acute myeloid leukemia with t(4;12)(q12;p13): A morphological dilemma
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Mayur Parihar, S R Arun, Umang V Patel, and Deepak Mishra
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Microbiology (medical) ,Pathology ,medicine.medical_specialty ,Myeloid ,pseudo lymphoid morphology ,CD34 ,lcsh:QR1-502 ,Lymphoproliferative disorders ,lcsh:Microbiology ,Pathology and Forensic Medicine ,Immunophenotyping ,dysplasia ,hemic and lymphatic diseases ,lcsh:Pathology ,Medicine ,Acute myeloid leukemia ,biology ,business.industry ,CD117 ,Myeloid leukemia ,General Medicine ,medicine.disease ,Leukemia ,medicine.anatomical_structure ,Dysplasia ,biology.protein ,t(4 ,12) ,business ,lcsh:RB1-214 - Abstract
Cytogenetics has a pivotal role in risk stratification of acute myeloid leukemia (AML). We report a case of AML with a t(4;12)(q12;p13). To the best of our knowledge, there are about 24 cases of t(4;12) reported in AML which are usually misdiagnosed as lymphoproliferative disorders on morphological assessment. This case showed specific clinical, morphological, and immunophenotypic features such as (1) pseudo lymphoid morphology, (2) dysplasia in granulocytic series, (3) an immature immunophenotype with positivity for CD34 and CD117, and (4) poor treatment response.
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- 2016
43. Etude des évènements génétiques associés à l'évolution du myélome multiple avec t(4;14)
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Song, Xiu Yi, Différenciation et progression tumorale des lymphocytes, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité, Jean-Christophe Bories, and STAR, ABES
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[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,T(4 ,PKD2 ,14) translocation ,14) ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Translocation t(4 - Abstract
Multiple myeloma (MM) is a hematological malignancy characterized by the proliferationof plasma cells in the bone marrow usually secreting a monoclonal immunoglobulin. Despite recenttherapeutic advances, the disease remains incurable, with a median survival of approximately 6years. However, there is considerable clinical heterogeneity between patients, with differentoutcome primarily associated with discrete genetic abnormalities. Among these, the t (4;14) (p16;q32), which is found in 15% of MM, defines one of the most serious subgroups of MM. Despite thepotential role of two deregulated oncogenes (FGFR3 and MMSET), the molecular mechanisms thatexplain the severity of MM with t (4;14) have not been clearly elucidated. By implementing theapproaches of molecular biology, high throughput sequencing and functional tests on a wide rangeof MM t (4;14), my project sought to identify genetic events associated with the poor prognosis ofthis subgroup of patients. The results showed that the site of the translocation breakpoints withinthe MMSET gene affect patient outcome. They also profiled the landscape of specific geneticmutations affecting t (4;14) MM, and revealed a relatively high frequency of alterations in the ATM/ ATR genes and PRKD2. Finally, this project has identified PKD2 as a therapeutic target anddemonstrated that an inhibitor of PKDs (kb NB 142-70) blocks the proliferation of MM cells in vitro.All these results throw new light on the pathophysiology of MM t (4;14) and opens the way to newtherapeutic approaches., Le myélome multiple (MM) est une hémopathie maligne, caractérisée par la prolifération au niveau de la moelle osseuse de plasmocytes tumoraux sécrétant le plus souvent une immunoglobuline monoclonale. Malgré de récents progrès thérapeutiques, cette maladie reste aujourd’hui incurable avec une survie médiane d’environ 6 ans. Cependant, il existe une grande hétérogénéité pronostique parmi les patients qui est associée à différentes anomalies génétiques. Parmi celles-ci, la translocation t(4;14) (p16;q32), retrouvée dans 15% des MM, définit l’une des formes de MM actuellement la plus grave. Malgré le rôle potentiel des deux oncogènes FGFR3 et MMSET qu’elle dérégule, les mécanismes moléculaires permettant d’expliquer la gravité des MM avec t(4;14) ne sont pas clairement élucidés. En mettant en œuvre des approches de biologie moléculaire, de séquençage à haut débit et de tests fonctionnels sur une très large série de MM t(4;14), mes travaux ont cherché à identifier les événements génétiques associés au mauvais pronostic de ce sous-groupe de malades. Les résultats montrent l’implication du point de cassure au sein du gène MMSET dans le pronostic des patients. Ils ont également permis de définir le paysage particulier des mutations génétiques affectant les MM t(4;14) en mettent en évidence les fréquences relativement élevées des altérations dans les gènes ATM/ATR et PRKD2. Enfin, ils ont identifiés PKD2 comme une cible thérapeutique et démontré qu’un inhibiteur des PKDs, kb NB 142-70, bloquait la prolifération des cellules de MM in vitro. L’ensemble de ces résultats jette un éclairage nouveau sur la physiopathologie des MM t(4;14) et ouvre la voie vers de nouvelles approches thérapeutiques.
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- 2017
44. t(4;11)(q21;p15), including one complex translocation t(1;4;11)(p32;q21;p15), in adult T-cell acute lymphoblastic leukemia
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Douet-Guilbert, Nathalie, Morel, Frédéric, Le Bris, Marie-Josée, Herry, Angèle, Le Calvez, Geneviève, Marion, Véronique, Berthou, Christian, and De Braekeleer, Marc
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- *
LYMPHOBLASTIC leukemia , *T cells - Abstract
We report two adults with T-cell acute lymphoblastic leukemia (ALL). Cytogenetic studies at diagnosis with R banding showed a 46,XX,t(4;11)(q21;p15)/46,XX karyotype in one patient and 46,XY,t(1;4;11)(p32;q21;p15)/46,XY in the other. Fluorescence in situ hybridization with whole chromosome paints (WCP1, WCP4, and WCP11) confirmed the complex rearrangement in the latter patient. Only 10 T-cell ALL patients with the t(4;11)(q21;p15) have been described, all, but one of them, being over 15 years old. Although recurrent in T-cell ALL, its frequency appears to be very low; indeed, it has been identified in only 4 of 193 adults and in 1 of 734 children with T-cell ALL thus far reported in the literature. [Copyright &y& Elsevier]
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- 2003
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45. Expression of MLL-AF4 or AF4-MLL fusions does not impact the efficiency of DNA damage repair
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Norma C. Gutiérrez, Aldeheid Bursen, Federico González, Julio Castaño, Pablo Menendez, Rolf Marschalek, Ana B. Herrero, European Commission, Generalitat de Catalunya, Fundación 'la Caixa', Josep Carreras Leukemia Foundation, Asociación Española Contra el Cáncer, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, and European Research Council
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0301 basic medicine ,DNA End-Joining Repair ,Oncogene Proteins, Fusion ,DNA damage ,Gene Expression ,AF4.MLL ,Biology ,DSB ,Histones ,03 medical and health sciences ,0302 clinical medicine ,PARP1 ,Radiation, Ionizing ,hemic and lymphatic diseases ,medicine ,Humans ,Secondary Acute Myeloid Leukemia ,DNA Breaks, Double-Stranded ,t(4 ,11) ,Homologous Recombination ,neoplasms ,Etoposide ,Genetics ,Ku70 ,MLL.AF4 ,Infant ,Cell Cycle Checkpoints ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Molecular biology ,3. Good health ,Comet assay ,Leukemia ,HEK293 Cells ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Comet Assay ,Infant leukemia ,Homologous recombination ,Myeloid-Lymphoid Leukemia Protein ,Research Paper ,DNA Damage ,medicine.drug - Abstract
The most frequent rearrangement of the human MLL gene fuses MLL to AF4 resulting in high-risk infant B-cell acute lymphoblastic leukemia (B-ALL). MLL fusions are also hallmark oncogenic events in secondary acute myeloid leukemia. They are a direct consequence of mis-repaired DNA double strand breaks (DNA-DSBs) due to defects in the DNA damage response associated with exposure to topoisomerase- II poisons such as etoposide. It has been suggested that MLL fusions render cells susceptible to additional chromosomal damage upon exposure to etoposide. Conversely, the genome-wide mutational landscape in MLL-rearranged infant B-ALL has been reported silent. Thus, whether MLL fusions compromise the recognition and/or repair of DNA damage remains unanswered. Here, the fusion proteins MLL-AF4 (MA4) and AF4-MLL (A4M) were CRISPR/Cas9-genome edited in the AAVS1 locus of HEK293 cells as a model to study MLL fusion-mediated DNA-DSB formation/repair. Repair kinetics of etoposide- and ionizing radiation-induced DSBs was identical in WT, MA4- and A4M-expressing cells, as revealed by flow cytometry, by immunoblot for γH2AX and by comet assay. Accordingly, no differences were observed between WT, MA4- and A4M-expressing cells in the presence of master proteins involved in non-homologous end-joining (NHEJ; i.e.KU86, KU70), alternative-NHEJ (Alt-NHEJ; i.e.LigIIIa, WRN and PARP1), and homologous recombination (HR, i.e.RAD51). Moreover, functional assays revealed identical NHEJ and HR efficiency irrespective of the genotype. Treatment with etoposide consistently induced cell cycle arrest in S/G2/M independent of MA4/A4M expression, revealing a proper activation of the DNA damage checkpoints. Collectively, expression of MA4 or A4M does neither influence DNA signaling nor DNA-DSB repair., This work was supported by the European Research Council to P.M (ERC-2014-CoG-646903), MINECO (SAF2013-43065 to P.M), The Foundation Inocente Inocente and the Spanish Association of Cancer Research (AECC) to P.M and the Deutsche José Carreras Leukämie Stiftung to R.M/P.M. P.M also acknowledges the financial support from The Obra Social La Caixa-Fundaciò Josep Carreras and The Generalitat de Catalunya (SGR330). F.G. is supported by a Ramón y Cajal Grant (RYC-2014-16751) from the Ministry of Economy and Competitiveness (MINECO), Spain. N.C.G and A.B.H acknowledge financial support from The Cooperative Research Thematic Networks (RTICC) (RD12/0036/0058) and the INNOCAMPUS Program (CEI10-1-0010).
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- 2016
46. Disentangling the microRNA regulatory milieu in multiple myeloma: integrative genomics analysis outlines mixed miRNA-TF circuits and pathway-derived networks modulated in t(4;14) patients
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Giovanni Tonon, Gareth J. Morgan, Chiara Romualdi, Gabriele Sales, Martina Manzoni, Stefania Bortoluzzi, Andrea Bisognin, Antonino Neri, Elisa Taiana, Luca Agnelli, Pierfrancesco Tassone, Enrica Calura, Katia Todoerti, and Nicola Amodio
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Translational research ,Protein Serine-Threonine Kinases ,Biology ,03 medical and health sciences ,0302 clinical medicine ,transciptional regulatory network ,Internal medicine ,14) translocation ,CEBPA ,microRNA ,medicine ,Humans ,Gene Regulatory Networks ,Hippo Signaling Pathway ,Prospective Studies ,Multiple myeloma ,Retrospective Studies ,Genetics ,Hematology ,expression profiling ,multiple myeloma ,t(4 ,Gene Expression Profiling ,medicine.disease ,Integrative genomics ,ErbB Receptors ,Gene expression profiling ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Core Binding Factor Alpha 2 Subunit ,Functional genomics ,Research Paper - Abstract
// Enrica Calura 1,* , Andrea Bisognin 2,* , Martina Manzoni 3 , Katia Todoerti 4 , Elisa Taiana 3 , Gabriele Sales 1 , Gareth J. Morgan 5 , Giovanni Tonon 6 , Nicola Amodio 7 , Pierfrancesco Tassone 7 , Antonino Neri 3 , Luca Agnelli 3,** , Chiara Romualdi 1,** and Stefania Bortoluzzi 2,** 1 Department of Biology, University of Padua, Padua, Italy 2 Department of Molecular Medicine, University of Padua, Padua, Italy 3 Department of Clinical Sciences and Community Health, University of Milan, and Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy 4 Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy 5 Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA 6 Functional Genomics of Cancer Unit, Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy 7 Department of Experimental and Clinical Medicine, University of Study Magna Graecia, Catanzaro, Italy * The first two authors equally contributed to this work ** A substantial contribution to the conception, design, execution and writing of this work was equally provided by these three groups. LA, CR, SB have therefore to be considered co-last authors Correspondence to: Luca Agnelli, email: // Keywords : multiple myeloma, transciptional regulatory network, t(4;14) translocation, microRNA, expression profiling Received : August 05, 2015 Accepted : September 30, 2015 Published : October 19, 2015 Abstract The identification of overexpressed miRNAs in multiple myeloma (MM) has progressively added a further level of complexity to MM biology. miRNA and gene expression profiles of two large representative MM datasets, available from retrospective and prospective series and encompassing a total of 249 patients at diagnosis, were analyzed by means of i n silico integrative genomics methods, based on MAGIA 2 and Micrographite computational procedures. We first identified relevant miRNA/transcription factors/target gene regulation circuits in the disease and linked them to biological processes. Members of the miR-99b/let-7e/miR-125a cluster, or of its paralog, upregulated in t(4;14), were connected with the specific transcription factors PBX1 and CEBPA and several target genes. These results were validated in two additional independent plasma cell tumor datasets. Then, we reconstructed a non-redundant miRNA-gene regulatory network in MM, linking miRNAs, such as let-7g , miR-19a , mirR-20a , mir-21 , miR-29 family, miR-34 family, miR-125b , miR-155 , miR-221 to pathways associated with MM subtypes, in particular the ErbB, the Hippo, and the Acute myeloid leukemia associated pathways.
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- 2016
47. DNA copy-number abnormalities do not occur in infant ALL with t(4;11)/MLL-AF4
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Silvia Bungaro, Marco Giordan, Grazia Fazio, G. De Rossi, Cristina Battaglia, L Corral, Giovanni Cazzaniga, R. Spinelli, Michela Bardini, Eleonora Mangano, Giuseppe Basso, Andrea Biondi, Ingrid Cifola, Bardini, M, Spinelli, R, Bungaro, S, Mangano, E, Corral, L, Cifola, I, Fazio, G, Giordan, M, Basso, G, De Rossi, G, Biondi, A, Battaglia, C, and Cazzaniga, G
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Male ,Cancer Research ,medicine.medical_specialty ,Oncogene Proteins, Fusion ,Gene Dosage ,Chromosomal translocation ,Disease ,Biology ,Polymorphism, Single Nucleotide ,infant ALL ,Translocation, Genetic ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,t(4 ,11) ,Genetics ,SNP arrays ,Hematology ,Chromosomes, Human, Pair 11 ,Cytogenetics ,Infant ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,DNA copy-number abnormalities ,Uniparental disomy ,Infant Acute Lymphoblastic Leukemia ,Leukemia ,Oncology ,Myeloid-Lymphoid Leukemia Protein ,MLL gene ,Female ,Chromosomes, Human, Pair 4 ,Human - Abstract
The pathogenesis of infant acute lymphoblastic leukemia (ALL) is still not well defined. Short latency to leukemia and very high concordance rate for ALL in Mixed-Lineage Leukemia (MLL)-positive infant twins suggest that the MLL rearrangement itself could be sufficient for overt leukemia. Attempts to generate a suitable mouse model for MLL-AF4-positive ALL did not thoroughly resolve the issue of whether cooperating mutations are required to reduce latency and to generate overt leukemia in vivo. In this study, we applied single-nucleotide polymorphism array technology to perform genomic profiling of 28 infant ALL cases carrying t(4;11) to detect MLL-cooperating aberrations hidden to conventional techniques and to gain new insights into infant ALL pathogenesis. In contrast to pediatric, adolescent and adult ALL cases, the MLL rearrangement in infant ALL is associated with an exceptionally low frequency of copy-number abnormalities, thus confirming the unique nature of this disease. By contrast, additional genetic aberrations are acquired at disease relapse. Small-segmental uniparental disomy traits were frequently detected, mostly constitutional, and widely distributed throughout the genome. It can be argued that the MLL rearrangement as a first hit, rather than inducing the acquisition of additional genetic lesions, has a major role to drive and hasten the onset of leukemia. Leukemia (2010) 24, 169-176; doi:10.1038/leu.2009.203; published online 12 November 2009
- Published
- 2009
48. Akut lenfoblastik lösemi hastalarında t(4;11) MLL/AF4 translokasyonunun real time RT-PCR ile 5 yıllık sonuçlarının retrospektif değerlendirilmesi
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SÜSLÜER, Sunde YILMAZ, KAYMAZ, Burçin Tezcanli, ÇETİNTAŞ, Vildan Bozok, VARDARLI, Aslı Tetik, AYGÜNEŞ, Duygu, DALMIZRAK, Ayşegül, AKTAN, Çağdaş, KÜÇÜKASLAN, Ali Şahin, BALCI, Tuğçe, KAYABAŞI, Çağla, YELKEN, Besra Özmen, GÜNEL, Nur Selvi, AVCI, Çığır Biray, KOSOVA, Buket, EROĞLU, Zuhal, AKSOYLAR, Serap, ÇETİNGÜL, Nazan, BALKAN, Can, YILMAZ, Deniz, AYDINOK, Yeşim, KAVAKLI, Kaan, TÖBÜ, Mahmut, TOMBULOĞLU, Murat, BÜYÜKKEÇECİ, Filiz, ŞAHİN, Fahri, SAYDAM, Güray, and GÜNDÜZ, Cumhur
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t(4 ,11) MLL-AF4 translokasyonu,gerçek zamanlı RT-PCR ,11) MLL-AF4 translocation,real time RT-PCR - Abstract
Aim: t(4,11) is a chromosomal abnormality formed by the translocation MLL-AF4, which is the result of the fusion of the AF4 gene, localized on 4q21 chromosomal band, to the MLL gene, localized on 11q23 chromosomal band. The aim of this study is to examine the results of the analysis of t (4;11) MLL-AF4 translocation in acute lymphoblastic leukemia (ALL) patients retrospectively. Materials and Methods: Peripheral blood or bone marrow samples of 176 children (70 girls, 106 boys) and 144 adults (60 women, 84 men) with a preliminary diagnosis of acute leukemia between 2009-2013 were analyzed in the Medical Biology Department of Ege University Faculty of Medicine. The translocation RNA results of 71 peripheral blood and 473 bone marrow samples of these patients were evaluated quantitatively for t(4;11) with real-time RT-PCR. t(4;11) quantitation was performed by real-time qRT-PCR instrument after the synthesis of complementary DNA with conventional PCR from total RNA or mRNA isolated from blood and bone marrow. Quantitative analysis of the patients was performed by comparing positive and negative controls and samples classified as positive or negative (the ratio of the number of positive copies to the number of reference copies). Results: A total of 320 patients, with 98 having also follow-ups, were evaluated for t(4;11) translocation. Totally 34 patients (24 children and 10 adults) were found positive and the other samples were negative. Conclusion: The assessment of these results supports that, quantitative determination of t(4;11) with RT-PCR method among newly diagnosed ALL patients and ALL patients undergoing treatment, is a valuable method for both confirming the diagnosis and guiding the treatment intended to achieve molecular remission., Amaç: t(4;11), MLL-AF4 translokasyonu sonucu oluşan, 4q21 kromozomal bandına yerleşim gösteren AF4 geninin 11q23 kromozomal bandına yerleşim gösteren MLL genine füzyonu sonucu gelişen kromozomal bir anomalidir. Bu çalışmada, retrospektif olarak 2009-2013 yılları arasındaki akut lenfoblastik lösemi (ALL) hastalarındaki t(4;11) MLL-AF4 translokasyonunun analiz sonuçlarının incelenmesi amaçlandı. Gereç ve Yöntem: Ege Üniversitesi Tıp Fakültesi Tıbbi Biyoloji Anabilim Dalı'na 2009-2013 yılları arasında akut lösemi ön tanısıyla 176 çocuk (70 kız, 106 erkek) ve 144 yetişkin (60 kadın, 84 erkek) olgunun kan veya kemik iliği örnekleri incelendi. Bu olgulara ait 71 kan ve 473 kemik iliği örneğinin t(4;11) translokasyon RNA sonuçları, gerçek zamanlı RT-PCR yöntemi ile kantitatif olarak değerlendirildi. İlk aşamada, kan ve kemik iliği örneklerinden izole edilen total RNA veya mRNA'dan konvansiyonel bir PCR cihazı ile komplementer DNA sentezlendi. İkinci aşamada, gerçek zamanlı PCR cihazı ile t(4;11) kantitasyonu gerçekleştirildi. Olguların kantitatif olarak değerlendirilmesi, pozitif kontrol ve negatif kontrolün karşılaştırılması ile örneklerin negatif yada pozitif (pozitif olgu kopya sayısının referans kopya sayısına oranı) olması şeklinde yapıldı. Bulgular: Çalışmamızda 98'i takip hastası olmak üzere toplam 320 hasta t(4;11) MLL-AF4 translokasyonu için değerlendirildi. Çalışmaların sonucunda toplam 34 olgu (24 çocuk, 10 yetişkin) pozitif ve diğer örnekler negatif olarak bulundu. Sonuç: Bu değerlendirmenin sonuçları, RT-PCR yöntemi ile ALL hastalarında yeni tanı döneminde ve tedavi sürecinde t(4;11) MLL-AF4 translokasyonunun kantitatif tayini, hem tanının kesinleştirilmesinde hem de moleküler remisyon sağlanmasına yönelik tedaviyi yönlendirmesinde değerli bir yöntem olduğunu desteklemektedir.
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- 2015
49. Unraveling the Activation Mechanism of Taspase1 which Controls the Oncogenic AF4-MLL Fusion Protein
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Tim Geppert, Eric Kowarz, Samaneh Sabiani, Rolf Marschalek, Gisbert Schneider, and Christian Engelbrecht
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Models, Molecular ,Multiprotein complex ,Oncogene Proteins, Fusion ,DNA Mutational Analysis ,Oncoprotein activation ,lcsh:Medicine ,Biology ,Crystallography, X-Ray ,Cleavage (embryo) ,t(4 ,11) leukemia ,Taspase1 ,AF4–MLL ,General Biochemistry, Genetics and Molecular Biology ,Leukemogenic ,Enzyme activator ,Genes, Reporter ,hemic and lymphatic diseases ,Endopeptidases ,Fluorescence Resonance Energy Transfer ,Humans ,Enzyme Assays ,lcsh:R5-920 ,Hydrolysis ,HEK 293 cells ,lcsh:R ,Reproducibility of Results ,General Medicine ,Fusion protein ,Molecular biology ,Enzyme Activation ,HEK293 Cells ,Mutagenesis, Site-Directed ,Myeloid-Lymphoid Leukemia Protein ,Mutant Proteins ,Original Article ,Protein Multimerization ,lcsh:Medicine (General) ,Transcription factor II A - Abstract
We have recently demonstrated that Taspase1-mediated cleavage of the AF4–MLL oncoprotein results in the formation of a stable multiprotein complex which forms the key event for the onset of acute proB leukemia in mice. Therefore, Taspase1 represents a conditional oncoprotein in the context of t(4;11) leukemia. In this report, we used site-directed mutagenesis to unravel the molecular events by which Taspase1 becomes sequentially activated. Monomeric pro-enzymes form dimers which are autocatalytically processed into the enzymatically active form of Taspase1 (αββα). The active enzyme cleaves only very few target proteins, e.g., MLL, MLL4 and TFIIA at their corresponding consensus cleavage sites (CSTasp1) as well as AF4–MLL in the case of leukemogenic translocation. This knowledge was translated into the design of a dominant-negative mutant of Taspase1 (dnTASP1). As expected, simultaneous expression of the leukemogenic AF4–MLL and dnTASP1 causes the disappearance of the leukemogenic oncoprotein, because the uncleaved AF4–MLL protein (328 kDa) is subject to proteasomal degradation, while the cleaved AF4–MLL forms a stable oncogenic multi-protein complex with a very long half-life. Moreover, coexpression of dnTASP1 with a BFP-CSTasp1-GFP FRET biosensor effectively inhibits cleavage. The impact of our findings on future drug development and potential treatment options for t(4;11) leukemia will be discussed., eBioMedicine, 2 (5), ISSN:2352-3964
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- 2015
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50. Phase 2 study of dovitinib in patients with relapsed or refractory multiple myeloma with or without t(4;14) translocation
- Abstract
Objectives: Approximately 15% of patients with multiple myeloma (MM) exhibit a t(4;14) translocation, which often results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3). This study evaluated the efficacy and safety of dovitinib, an RTK inhibitor with in vitro inhibitory activity against FGFR, in patients with re
- Published
- 2015
- Full Text
- View/download PDF
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