769 results on '"Acute megakaryoblastic leukemia"'
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2. Vorinostat and Azacitidine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia
- Published
- 2024
3. Liver fibrosis among infants with t(1;22)(p13;q13) acute megakaryoblastic leukemia: a case report and literature review.
- Author
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Arad-Cohen, Nira, Attias, Ori, Zohar, Yaniv, and Messinger, Yoav H.
- Abstract
This case report describes a 2-month-old girl with acute megakaryoblastic leukemia (AMKL) harboring the t(1;22)(p13;q13) translocation, resulting in the RBM15::MRTFA fusion gene. She presented with massive hepatosplenomegaly and liver fibrosis and achieved complete remission with chemotherapy; the liver fibrosis resolved within 2.5 months. After 12 years of follow-up, the patient remained in good health, without relapse. Reviewing the literature on eight additional similar cases of liver fibrosis, this subtype of AMKL predominantly affects female patients below 3 months of age, with a median onset at 6 weeks. High rates of severe complications were observed, with five of nine patients dying within 10 weeks of diagnosis. The authors hypothesized that the proliferation of abnormal megakaryoblasts within the liver leads to the release of profibrotic cytokines, such as TGF-b1, which induces liver fibrosis similar to that observed in transient abnormal myelopoiesis in Down syndrome. Careful monitoring of liver functions and reduced-intensity chemotherapy are recommended for this very young patient population. Nonetheless, long-term survival can be achieved with aggressive supportive care and treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
4. Immunophenotypic markers for the evaluation of minimal/measurable residual disease in acute megakaryoblastic leukemia
- Author
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Carina Maria Pinto, Camila Marques Bertolucci, Alef Rafael Severino, Juliana Fernanda dos Santos Tosi, and Maura R V Ikoma-Colturato
- Subjects
Acute megakaryoblastic leukemia ,Minimal/measurable residual disease ,Flow cytometry ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Acute megakaryoblastic leukemia is characterized by heterogeneous biology and clinical behavior. Immunophenotypic characteristics include the expression of megakaryocytic differentiation markers (e.g. CD41, CD42a, CD42b, CD61) associated with immaturity markers (CD34, CD117, HLA-DR) and myeloid markers (e.g. CD13, CD33) and even with lymphoid cross-lineage markers (e.g. CD7, CD56). Although the diagnostic immunophenotype has already been well described, given the rarity of the disease, its immunophenotypic heterogeneity and post-therapeutic instability, there is no consensus on the combination of monoclonal markers to detect minimal/measurable residual disease (MRD).Currently, MRD is an important tool for assessing treatment efficacy and prognostic risk. In this study, we evaluated the immunophenotypic profile of MRD in a retrospective cohort of patients diagnosed with acute megakaryoblastic leukemia, to identify which markers, positive or negative, were more stable after treatment and which could be useful for MRD evaluation. The expression profile of each marker was evaluated in sequential MRD samples. In conclusion, the markers evaluated in this study can be combined in an MRD immunophenotypic panel to investigate for megakaryoblastic leukemia. Although this study is retrospective and some data are missing, the information obtained may contribute to prospective studies to validate more specific strategies in the detection of MRD in acute megakaryoblastic leukemia.
- Published
- 2024
- Full Text
- View/download PDF
5. Donor Natural Killer Cells and Donor Stem Cell Transplant in Treating Patients With High Risk Myeloid Malignancies
- Author
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National Cancer Institute (NCI)
- Published
- 2023
6. Liver fibrosis among infants with t(1;22)(p13;q13) acute megakaryoblastic leukemia: a case report and literature review
- Author
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Nira Arad-Cohen, Ori Attias, Yaniv Zohar, and Yoav H. Messinger
- Subjects
acute megakaryoblastic leukemia ,non-Down ,liver fibrosis ,pediatric ,t(1 ,22)(p13 ,q13) translocation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
This case report describes a 2-month-old girl with acute megakaryoblastic leukemia (AMKL) harboring the t(1;22)(p13;q13) translocation, resulting in the RBM15::MRTFA fusion gene. She presented with massive hepatosplenomegaly and liver fibrosis and achieved complete remission with chemotherapy; the liver fibrosis resolved within 2.5 months. After 12 years of follow-up, the patient remained in good health, without relapse. Reviewing the literature on eight additional similar cases of liver fibrosis, this subtype of AMKL predominantly affects female patients below 3 months of age, with a median onset at 6 weeks. High rates of severe complications were observed, with five of nine patients dying within 10 weeks of diagnosis. The authors hypothesized that the proliferation of abnormal megakaryoblasts within the liver leads to the release of profibrotic cytokines, such as TGF-β1, which induces liver fibrosis similar to that observed in transient abnormal myelopoiesis in Down syndrome. Careful monitoring of liver functions and reduced-intensity chemotherapy are recommended for this very young patient population. Nonetheless, long-term survival can be achieved with aggressive supportive care and treatment.
- Published
- 2024
- Full Text
- View/download PDF
7. Skin Manifestations of Micafungin Breakthrough Disseminated Trichosporonosis in Acute Megakaryoblastic Leukemia: A Case Report.
- Author
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Yukiro Matsumoto, Sayuka Arakawa, Ken Sadahira, Tomotaka Sato, Kazuto Yamazaki, and Shuhei Nishimoto
- Subjects
- *
CUTANEOUS manifestations of general diseases , *ACUTE leukemia , *HEMATOLOGIC malignancies , *ANTIFUNGAL agents , *BREAKTHROUGH infections , *MUCORMYCOSIS - Abstract
Disseminated trichosporonosis is a rare fungal infection whose risk factors are hematological malignancies and neutropenia. Recently, breakthrough Trichosporon infections after administration of micafungin, the first-line systemic antifungal agent in compromised hosts, have been widely recognized. A man in his seventies about 1 month into chemotherapy for acute megakaryoblastic leukemia presented with a worsening fever and dyspnea. The patient was being administered with empirical micafungin therapy for suspected candidiasis. As the symptoms progressed, scattered erythema appeared on the trunk, some with a dark red vesicle at the center. Blood cultures identified Trichosporon asahii, as did the specimen of the skin biopsy. On the basis also of the presence of pneumonia on chest computed tomography, we confirmed the diagnosis of disseminated trichosporonosis and changed the antifungal agent from micafungin to voriconazole. Blood culture turned out to be negative 1 month after administrating voriconazole. However, the patient died of the leukemia. Our review of previous reports on cutaneous manifestations of disseminated trichosporonosis revealed that despite their morphological diversity, erythema with a red papule or vesicle at the center, implying necrosis, was also observed in previous cases. Our case report suggests that dermatologists should be aware of skin manifestations of disseminated trichosporonosis after micafungin administration, especially in cases of hematological malignancies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
8. Acute monocytic leukemia with KMT2A::LASP1 developed 9 months after diagnosis of acute megakaryoblastic leukemia in a 2-year-old boy.
- Author
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Fujita, Takashi, Fukushima, Hiroko, Nanmoku, Toru, Arakawa, Yuki, Deguchi, Takao, Suzuki, Ryoko, Yamaki, Yuni, Hosaka, Sho, and Takada, Hidetoshi
- Abstract
Acute myeloid leukemia (AML) is known as one of the subsequent malignant neoplasms that can develop after cancer treatment, but it is difficult to distinguish from relapse when the preceding cancer is leukemia. We report a 2-year-old boy who developed acute megakaryoblastic leukemia (AMKL, French-American-British classification [FAB]: M7) at 18 months of age and achieved complete remission with multi-agent chemotherapy without hematopoietic stem cell transplantation. Nine months after diagnosis and 4 months after completing treatment for AMKL, he developed acute monocytic leukemia (AMoL) with the KMT2A::LASP1 chimeric gene (FAB: M5b). The second complete remission was achieved using multi-agent chemotherapy and he underwent cord blood transplantation 4 months after AMoL was diagnosed. He is currently alive and disease free at 39 and 48 months since his AMoL and AMKL diagnoses, respectively. Retrospective analysis revealed that the KMT2A::LASP1 chimeric gene was detected 4 months after diagnosis of AMKL. Common somatic mutations were not detected in AMKL or AMoL and no germline pathogenic variants were detected. Since the patient's AMoL was different from his primary leukemia of AMKL in terms of morphological, genomic, and molecular analysis, we concluded that he developed a subsequent leukemia rather than a relapse of his primary leukemia. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
9. Cryptic KMT2A/MLLT10 fusion detected by next-generation sequencing in a case of pediatric acute megakaryoblastic leukemia.
- Author
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Kim, Yeseul, Kim, Boram, Seong, Moon-Woo, Lee, Dong Soon, Hong, Kyung Taek, Kang, Hyoung Jin, Yun, Jiwon, and Chang, Yoon Hwan
- Subjects
- *
ACUTE leukemia , *CHROMOSOME analysis , *FLUORESCENCE in situ hybridization , *CHILD patients , *GENE rearrangement , *CYTOGENETICS , *NUCLEOTIDE sequencing - Abstract
• A cryptic KMT2A/MLLT10 rearrangement was detected in a pediatric patient with acute megakaryoblastic leukemia. • NGS detected the cryptic gene fusion, not detected by traditional chromosome studies. • In this cryptic KMT2A/MLLT10 fusion, a part of MLLT10 was inserted into KMT2A. KMT2A (11q23.3) gene rearrangements are found in acute leukemia and are associated with a poor or intermediate prognosis. MLLT10 is the fourth most common gene fusion partner for KMT2A. A reciprocal translocation t(10;11) is insufficient to produce an in-frame KMT2A/MLLT10 fusion, because the genes involved in the rearrangement have opposite transcriptional orientations. In order to bring KMT2A and MLLT10 into juxtaposition, complex rearrangements are required. Until now, conventional chromosome, fluorescence in situ hybridization (FISH), and reverse transcriptase-polymerase chain reaction (RT-PCR) studies have been used to detect KMT2A/MLLT10 fusions. However, conventional studies have limitations, such as poor and inconsistent resolution, when compared to next-generation sequencing (NGS). In this study, we report a pediatric patient with acute megakaryoblastic leukemia, in whom the cryptic KMT2A/MLLT10 fusion was not detected by KMT2A break-apart probe FISH and chromosome analysis, but detected by NGS. In this patient, NGS showed cryptic insertion of MLLT10 exons 9-24 into intron 9 of KMT2A , resulting in a KMT2A/MLLT10 fusion. Therefore, NGS is a valuable complementary option for the evaluation of structural aberrations, especially those with a cryptic size. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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10. Myeloid Leukemia of Down Syndrome.
- Author
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Kosmidou, Aikaterini, Tragiannidis, Athanasios, and Gavriilaki, Eleni
- Subjects
- *
CARDIOTOXICITY , *GENETIC mutation , *DOWN syndrome , *MYELOID leukemia , *CHROMOSOME abnormalities , *HEMATOPOIESIS , *TRANSCRIPTION factors , *CYTARABINE , *CYTOGENETICS - Abstract
Simple Summary: Patients with Down Syndrome have been thoroughly studied over the past 100 years, and many attempts have been made to attain insight into the developmental biology of DS. Given the association of DS with several hematological disorders, it was more than appealing to us to conduct a literature research to identify the rare subtype of acute myeloid leukemias associated with DS -Myeloid Leukemia of Down Syndrome- to investigate its occurrence, clinical presentation, and typical characteristics in terms of blast morphology and immunophenotype, and suggest optimal criteria for early diagnosis and progression monitoring. Among others, the multistep clonal evolution process is being analyzed here, while challenges on treatment of those patients are presented in detail. We suggested that a standardized holistic approach of care for children with Myeloid Leukemia of Down Syndrome should be ensured and applied to provide more enhanced outcomes to those patients. Myeloid leukemia of Down syndrome (ML-DS) is characterized by a distinct natural history and is classified by the World Health Organization (WHO) as an independent entity, occurring with unique clinical and molecular features. The presence of a long preleukemic, myelodysplastic phase, called transient abnormal myelopoiesis (TAM), precedes the initiation of ML-DS and is defined by unusual chromosomal findings. Individuals with constitutional trisomy 21 have a profound dosage imbalance in the hematopoiesis-governing genes located on chromosome 21 and thus are subject to impaired fetal as well as to neonatal erythro-megakaryopoiesis. Almost all neonates with DS develop quantitative and morphological hematological abnormalities, yet still only 5–10% of them present with one of the preleukemic or leukemic conditions of DS. The acquired mutations in the key hematopoietic transcription factor gene GATA1, found solely in cells trisomic for chromosome 21, are considered to be the essential step for the selective growth advantage of leukemic cells. While the majority of cases of TAM remain clinically 'silent' or undergo spontaneous remission, the remaining 20% to 30% of them progress into ML-DS until the age of 4 years. The hypersensitivity of ML-DS blasts to chemotherapeutic agents, including but not limited to cytarabine, and drugs' increased infectious and cardiac toxicity have necessitated the development of risk-adapted treatment protocols for children with ML-DS. Recent advances in cytogenetics and specific molecular mechanisms involved in the evolution of TAM and ML-DS are reviewed here, as well as their integration in the improvement of risk stratification and targeted management of ML-DS. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
11. Myeloid sarcoma with RBM15::MRTFA (MKL1) mimicking vascular neoplasm
- Author
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Gündoğdu, Fatma, Agaimy, Abbas, Aytaç, Selin, Hazar, Volkan, Üner, Ayşegül, and Kösemehmetoğlu, Kemal
- Published
- 2024
- Full Text
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12. Features of acute megakaryoblastic leukemia diagnosis in a child with Down syndrome
- Author
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N. K. Guskova, O. N. Selyutina, I. B. Lysenko, Yu. Yu. Kozel, O. V. Kozyuk, V. V. Dmitrieva, M. A. Baranenkova, and A. S. Nozdricheva
- Subjects
down syndrome ,acute myeloid leukemia ,acute megakaryoblastic leukemia ,morphological examination of the bone marrow ,flow cytometry ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
We present a description of the difficulties in diagnosing acute megakaryoblastic leukemia in a child with Down syndrome aggravated by multiple comorbidities. In this case, a comprehensive assessment of clinical data, the results of an automatic complete blood count with a detailed interpretation of the entire range of parameters, as well as morphological and immunophenotypic bone marrow examination using an extended panel of monoclonal antibodies played a key role in the diagnosis.
- Published
- 2023
- Full Text
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13. Gene mutation landscape of a rare patient with acute megakaryoblastic leukemia after treatment of intracranial germ cell tumor.
- Author
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Li-Xin Wang, Wei-Jie Liao, Yu-Hua Jiang, Chao Chen, Wang-Sheng Lu, Feng Yin, and Hao-Yong Ning
- Subjects
GENETIC mutation ,ACUTE leukemia ,GERM cell tumors ,HEMATOLOGIC malignancies ,PROGENITOR cells - Abstract
Introduction: It was first reported that germ cell tumor patients suffer from hematologic malignancies 37 years ago. Since then, the number of relevant reports has increased each year, with most cases being mediastinal germ cell tumor. Theories have been proposed to explain this phenomenon, including a shared origin of progenitor cells, the effects of treatment, and independent development. However, up to now, no widely accepted explanation exists. The case with acute megakaryoblastic leukemia and intracranial germ cell tumor has never been reported before and the association is far less known. Methods: We used whole exome sequencing and gene mutation analysis to study the relationship between intracranial germ cell tumor and acute megakaryoblastic leukemia of our patient. Results: We report a patient who developed acute megakaryoblastic leukemia after treatment for an intracranial germ cell tumor. Through whole exome sequencing and gene mutation analysis, we identified that both tumors shared the same mutation genes and mutation sites, suggesting they originated from the same progenitor cells and differentiated in the later stage. Discussion: Our findings provide the first evidence supporting the theory that acute megakaryoblastic leukemia and intracranial germ cell tumor has the same progenitor cells. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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14. Lineage switch in a pediatric patient with KMT2A-MLLT3 from acute megakaryoblastic leukemia to T cell acute lymphoblastic leukemia at the fourth relapse after allo-HSCT: with literature review.
- Author
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Gao, Li, Lu, Jun, Li, Jie, Hu, Yixin, Lu, Ye, Du, Weiwei, and Hu, Shaoyan
- Abstract
We present a patient with acute megakaryoblastic leukemia (AMKL) harboring KMT2A-MLLT3 that converted to T cell acute lymphoblastic leukemia (T-ALL) at her fourth relapse. A 4-year-old girl developed AMKL with multiple swollen lymph nodes. She exhibited several recurrences in the bone marrow and died of septic shock after her fourth relapse. Bone marrow cells at the initial diagnosis and at all four relapses had the same KMT2A-MLLT3 fusion transcript. She also developed a somatic mutation (c.7177C > T p.Q2393X) of NOTCH1 at the fourth relapse. This sequential phenotypic and cytogenetic study may yield valuable insights into the mechanism of AMKL to T-ALL lineage switch and possible implications for treatment selection. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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15. Alisertib in Treating Patients With Myelofibrosis or Relapsed or Refractory Acute Megakaryoblastic Leukemia
- Author
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The Leukemia and Lymphoma Society, Millennium Pharmaceuticals, Inc., National Cancer Institute (NCI), and Brady Stein, Principal Investigator
- Published
- 2021
16. Unmanipulated haploidentical hematopoietic stem cell transplantation for pediatric de novo acute megakaryoblastic leukemia without Down syndrome in China: A single-center study.
- Author
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Junbin Huang, Guanhua Hu, Pan Suo, Lu Bai, Yifei Cheng, Yu Wang, XiaoHui Zhang, KaiYan Liu, Yu Qian Sun, Lan Ping Xu, Jun Kong, Chen Hua Yan, and Xiaojun Huang
- Subjects
HEMATOPOIETIC stem cell transplantation ,STEM cell transplantation ,ACUTE leukemia ,DOWN syndrome ,BRONCHIOLITIS obliterans ,BRONCHIOLITIS ,BLOOD diseases - Abstract
Background: AMKL without DS is a rare but aggressive hematological malignant disease in children, and it is associated with inferior outcomes. Several researchers have regarded pediatric AMKL without DS as high-risk or at least intermediate-risk AML and proposed that upfront allogenic hematopoietic stem cell transplantation (HSCT) in first complete remission might improve long-term survival. Patients and method: We conducted a retrospective study with twenty-five pediatric (< 14 years old) AMKL patients without DS who underwent haploidentical HSCT in the Peking University Institute of Hematology, Peking University People's Hospital from July 2016 to July 2021. The diagnostic criteria of AMKL without DS were adapted from the FAB and WHO: = 20% blasts in the bone marrow, and those blasts expressed at least one or more of the platelet glycoproteins: CD41, CD61, or CD42. AMKL with DS and therapy related AML was excluded. Children without a suitable closely HLA-matched related or unrelated donor (donors with more than nine out of 10 matching HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ loci), were eligible to receive haploidentical HSCT. Definition was adapted from international cooperation group. All statistical tests were conducted with SPSS v.24 and R v.3.6.3. Results: The 2-year OS was 54.5 ± 10.3%, and the EFS was 50.9 ± 10.2% in pediatric AMKL without DS undergoing haplo-HSCT. Statistically significantly better EFS was observed in patients with trisomy 19 than in patients without trisomy 19 (80 ± 12.6% and 33.3 ± 12.2%, respectively, P = 0.045), and OS was better in patients with trisomy 19 but with no statistical significance (P = 0.114). MRD negative pre-HSCT patients showed a better OS and EFS than those who were positive (P < 0.001 and P = 0.003, respectively). Eleven patients relapsed post HSCT. The median time to relapse post HSCT was 2.1 months (range: 1.0-14.4 months). The 2-year cumulative incidence of relapse (CIR) was 46.1 ± 11.6%. One patient developed bronchiolitis obliterans and respiratory failure and died at d + 98 post HSCT. Conclusion: AMKL without DS is a rare but aggressive hematological malignant disease in children, and it is associated with inferior outcomes. Trisomy 19 and MRD negative pre-HSCT might contribute to a better EFS and OS. Our TRM was low, haplo-HSCT might be an option for high-risk AMKL without DS. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
17. Advances in molecular characterization of myeloid proliferations associated with Down syndrome.
- Author
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Jixia Li and Kalev-Zylinska, Maggie L.
- Subjects
DOWN syndrome ,SOMATIC mutation ,ACUTE myeloid leukemia ,MYELOID leukemia ,MICRORNA - Abstract
Myeloid leukemia associated with Down syndrome (ML-DS) has a unique molecular landscape that differs from other subtypes of acute myeloid leukemia. ML-DS is often preceded by a myeloproliferative neoplastic condition called transient abnormal myelopoiesis (TAM) that disrupts megakaryocytic and erythroid differentiation. Over the last two decades, many genetic and epigenetic changes in TAM and ML-DS have been elucidated. These include overexpression of molecules and micro-RNAs located on chromosome 21, GATA1 mutations, and a range of other somatic mutations and chromosomal alterations. In this review, we summarize molecular changes reported in TAM and ML-DS and provide a comprehensive discussion of these findings. Recent advances in the development of CRISPR/Cas9-modified induced pluripotent stem cell-based disease models are also highlighted. However, despite significant progress in this area, we still do not fully understand the pathogenesis of ML-DS, and there are no targeted therapies. Initial diagnosis of ML-DS has a favorable prognosis, but refractory and relapsed disease can be difficult to treat; therapeutic options are limited in Down syndrome children by their stronger sensitivity to the toxic effects of chemotherapy. Because of the rarity of TAM and ML-DS, large-scale multicenter studies would be helpful to advance molecular characterization of these diseases at different stages of development and progression. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
18. Revealing the intratumoral heterogeneity of non-DS acute megakaryoblastic leukemia in single-cell resolution.
- Author
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Narun Su, Zifeng Li, Jiapeng Yang, Yang Fu, Xiaohua Zhu, Hui Miao, Yi Yu, Wenjin Jiang, Jun Le, Xiaowen Qian, Hongsheng Wang, Maoxiang Qian, and Xiaowen Zhai
- Subjects
ACUTE leukemia ,FETAL liver cells ,ACUTE myeloid leukemia ,HETEROGENEITY ,RNA sequencing - Abstract
Pediatric acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) characterized by abnormal megakaryoblasts, and it is divided into the AMKL patients with Down syndrome (DS-AMKL) and AMKL patients without DS (non-DS-AMKL). Pediatric non-DS-AMKL is a heterogeneous disease with extremely poor outcome. We performed singlecell RNA sequencing (scRNA-seq) of the bone marrow from two CBFA2T3-GLIS2 fusion-positive and one RBM15-MKL1 fusion-positive non-DS-AMKL children. Meanwhile, we downloaded the scRNA-seq data of normal megakaryocyte (MK) cells of the fetal liver and bone marrow from healthy donors as normal controls. We conducted cell clustering, cell-type identification, inferCNV analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and Monocle2 analysis to investigate the intratumoral heterogeneity of AMKL. Using canonical markers, we identified and characterized the abnormal blasts and other normal immune cells from three AMKL samples. We found intratumoral heterogeneity of AMKL in various cell-type proportions, malignant cells' diverse copy number variations (CNVs), maturities, significant genes expressions, and enriched pathways. We also identified potential markers for pediatric AMKL, namely, RACK1, ELOB, TRIR, NOP53, SELENOH, and CD81. Our work offered insight into the heterogeneity of pediatric acute megakaryoblastic leukemia and established the single-cell transcriptomic landscape of AMKL for the first time. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
19. Myeloid Leukemia of Down Syndrome
- Author
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Aikaterini Kosmidou, Athanasios Tragiannidis, and Eleni Gavriilaki
- Subjects
Down syndrome ,myeloid leukemia ,acute megakaryoblastic leukemia ,transient abnormal myelopoiesis ,GATA1 gene ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Myeloid leukemia of Down syndrome (ML-DS) is characterized by a distinct natural history and is classified by the World Health Organization (WHO) as an independent entity, occurring with unique clinical and molecular features. The presence of a long preleukemic, myelodysplastic phase, called transient abnormal myelopoiesis (TAM), precedes the initiation of ML-DS and is defined by unusual chromosomal findings. Individuals with constitutional trisomy 21 have a profound dosage imbalance in the hematopoiesis-governing genes located on chromosome 21 and thus are subject to impaired fetal as well as to neonatal erythro-megakaryopoiesis. Almost all neonates with DS develop quantitative and morphological hematological abnormalities, yet still only 5–10% of them present with one of the preleukemic or leukemic conditions of DS. The acquired mutations in the key hematopoietic transcription factor gene GATA1, found solely in cells trisomic for chromosome 21, are considered to be the essential step for the selective growth advantage of leukemic cells. While the majority of cases of TAM remain clinically ‘silent’ or undergo spontaneous remission, the remaining 20% to 30% of them progress into ML-DS until the age of 4 years. The hypersensitivity of ML-DS blasts to chemotherapeutic agents, including but not limited to cytarabine, and drugs’ increased infectious and cardiac toxicity have necessitated the development of risk-adapted treatment protocols for children with ML-DS. Recent advances in cytogenetics and specific molecular mechanisms involved in the evolution of TAM and ML-DS are reviewed here, as well as their integration in the improvement of risk stratification and targeted management of ML-DS.
- Published
- 2023
- Full Text
- View/download PDF
20. Profile of down syndrome–associated malignancies: Epidemiology, clinical features and therapeutic aspects
- Author
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Akira Shimada
- Subjects
Down syndrome ,Acute myeloid leukemia ,Acute megakaryoblastic leukemia ,Transient abnormal myelopoiesis ,Acute lymphoblastic leukemia ,Solid tumor ,Pediatrics ,RJ1-570 - Abstract
Down syndrome (DS) is a congenital chromosomal abnormality caused by the presence of all or part of a third copy of chromosome 21 (+21). DS is frequently complicated by congenital heart or digestive tract diseases at birth. DS patients are prone to infections and have mental retardation, with dementia such as Alzheimer's disease showing in later life. Furthermore, malignancies with specific characteristics are also highly reported in DS patients compared with non-DS patients. Therefore, DS is believed to be a cancer predisposition syndrome due to the chromosomal instability. Acute myeloid leukemia (AML) and especially acute megakaryoblastic leukemia (AMKL) by French-American-British (FAB) classification are the most frequent hematological malignancies in DS patients, occurring at a rate that is 500 times higher than that in non-DS patients. Interestingly, transient abnormal myelopoiesis (TAM) is observed in approximately 10% of DS neonates with GATA1 mutations, and most TAM patients are asymptomatic and show spontaneous regression; however, about 10%–20% of TAM cases are fatal because of complications such as fetal effusion, liver fibrosis, and other complications.Acute lymphoblastic leukemia (ALL) is also associated with DS, occurring at a rate that is 20 times higher than that in non-DS patients. Furthermore, the prognosis of DS-ALL patients is poorer than that of non-DS-ALL patients. A recent genetic analysis revealed that more than half of DS-ALL cases have a mutation in the CRLF2–JAK pathway, indicating that JAK inhibitors might have a limited effect for DS-ALL patients.Notably, solid tumors such as neuroblastoma, Wilms tumor, and brain tumor, which are frequently observed in non-DS children, are rarely reported in DS children. The reason remains unknown, but it may be because of the triplication of the Down syndrome critical region 1 (DSCR1) gene on chromosome 21. In adult patients with DS, the expected age-adjusted incidence rates of solid tumors are low compared with age-matched euploid cohorts for most cancers except for testicular cancer. Although the average life expectancy of patients with DS will increase with advances in healthcare, the detailed health problems including cancer rates in older DS patients remain unknown. Therefore, these issues will be needed to be addressed in future studies.
- Published
- 2021
- Full Text
- View/download PDF
21. Detection and monitoring of minimal residual disease in acute megakaryoblastic leukemia in children
- Author
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Alexandra D. Palladina, Aleksandr V. Popa, Timur T. Valiev, Valentin G. Nikitaev, Olga A. Chernysheva, Natalia A. Kupryshina, Irina N. Serebryakova, Tamara V. Shvedova, Konstantin L. Kondratchik, and Nikolai N. Tupitsyn
- Subjects
acute megakaryoblastic leukemia ,m7 ,minimal residual disease ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML), which is associated with poor prognosis for all patients except children with t(1;22) or Down syndrome. The frequency of complete remission in case of AMKL is comparable to the frequency of complete remission in other variants of AML, and the median survival is much lower. This determines the necessity to update criteria for assessment of the effect of treatment using flow cytometry definition of the level of minimal residual disease (MRD). Nowadays, there are no unified and standardized approaches for the measurement of MRD in case of myeloid leukemia, including AMKL, which prohibits adequate assessment of the therapy effect and in some cases determination of the indications for allogeneic hematopoietic stem cells transplantation. The article identifies diagnostic features and describes approaches for the measurement of the level of MRD in case of AMKL. Aim. The aim is to demonstrate the algorithms for diagnosing and measuring MRD in case of AML-M7 in children. Materials and methods. The article analyzes the clinical and immunological profile of 10 boys and 4 girls with the initial diagnosis of AMKL between the ages of 3 months 12 years old, 13 of them have received treatment in the FSBI N.N. Blokhin National Medical Research Center of Oncology and one in the GBUZ Morozovsky DGKB between 1995 and 2020, The measurement of MRD was carried out in 6 patients. The measurement of MRD was carried out using both morphocytochemical method and multiparameter flow cytometry with megakaryocyte markers (CD61, CD42, CD41) in combination with other myeloid markers (CD13, CD33), CD34, CD117 and aberrant markers (mainly CD7). Results. We showed that adequate measurement of the level of MRD had required detailed immunophenotyping during diagnosis to determine the aberration of megakaryoblasts. CD9 marker (100%), CD33 myeloid marker (69.2%), stem cell antigen CD34 (46.2%), CD13 (38.2%) in addition to megakaryocyte markers (100%) were most often expressed on blast cells in case of AMKL. The CD117 antigen was present on the blasts in 33.3% of cases. The expression of the T-cell-associated CD7 antigen (46.2%) was frequent. The measurement of MRD was carried out during the treatment (usually after an induction course) on the basis of the markers of megakaryocytic cell line (CD61, CD41, CD42a, CD42b), weak CD45 expression, as well as the immunophenotype characteristics during initial diagnosis. The level of MRD ranged from completely negative (0%; 0.006%) to evident (1.05%). Conclusion. The detection of residual tumor megakaryoblasts in case of AML-M7 using flow cytometry is a promising method to evaluate the effect of therapy. The adequate measurement of the level of MRD requires detailed immunophenotyping during the diagnosis to determine the aberration of megakaryoblasts.
- Published
- 2021
- Full Text
- View/download PDF
22. Case Report: The Value of Genomic Analysis in a Case of Megakaryoblastic Leukemia With Atypical Initial Manifestation
- Author
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Miriam Gutiérrez-Jimeno, Elena Panizo-Morgado, Marta Calvo-Imirizaldu, Víctor Galán-Gómez, Adela Escudero-López, and Ana Patiño-García
- Subjects
extramedullary acute myeloid leukemia ,myeloid sarcoma ,acute megakaryoblastic leukemia ,genomics ,next generation sequencing ,Pediatrics ,RJ1-570 - Abstract
We report the case of a 7-month-old female patient who developed acute megakaryoblastic leukemia 6 months after the appearance of skull bone lesions. Initial evaluation and diagnosis of this patient were challenging and only achieved thanks to genomic analysis by NGS (next generation sequencing). It is unusual for the initial manifestation of acute megakaryoblastic leukemia to be a skull bone lesion. Extramedullary acute myeloid leukemia (eAML), also known as myeloid sarcoma (MS), often occurs simultaneously with acute myeloid leukemia (AML), although it may precede AML. Genomic analysis based on a NGS panel (Oncomine Childhood Cancer Research Assay) detected a RBM15::MKL1 fusion, a consequence of a t (1;22)(p13;q13) translocation, establishing the diagnosis of acute megakaryoblastic leukemia and enabling disease follow-up by qPCR. A diagnosis of eAML is built up from various findings in radiological, histological, immunophenotypic and genomic studies; when the tumor appears de novo, diagnosis is more complicated. We emphasize the importance of a multidisciplinary team in the initial approach to rare tumors and the use of genomic studies to contribute to the knowledge of these neoplasms, risk stratification and treatment planning.
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- 2022
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23. Immunophenotypic markers for the evaluation of minimal/measurable residual disease in acute megakaryoblastic leukemia.
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Pinto CM, Bertolucci CM, Severino AR, Dos Santos Tosi JF, and Ikoma-Colturato MRV
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Acute megakaryoblastic leukemia is characterized by heterogeneous biology and clinical behavior. Immunophenotypic characteristics include the expression of megakaryocytic differentiation markers (e.g. CD41, CD42a, CD42b, CD61) associated with immaturity markers (CD34, CD117, HLA-DR) and myeloid markers (e.g. CD13, CD33) and even with lymphoid cross-lineage markers (e.g. CD7, CD56). Although the diagnostic immunophenotype has already been well described, given the rarity of the disease, its immunophenotypic heterogeneity and post-therapeutic instability, there is no consensus on the combination of monoclonal markers to detect minimal/measurable residual disease (MRD). Currently, MRD is an important tool for assessing treatment efficacy and prognostic risk. In this study, we evaluated the immunophenotypic profile of MRD in a retrospective cohort of patients diagnosed with acute megakaryoblastic leukemia, to identify which markers, positive or negative, were more stable after treatment and which could be useful for MRD evaluation. The expression profile of each marker was evaluated in sequential MRD samples. In conclusion, the markers evaluated in this study can be combined in an MRD immunophenotypic panel to investigate for megakaryoblastic leukemia. Although this study is retrospective and some data are missing, the information obtained may contribute to prospective studies to validate more specific strategies in the detection of MRD in acute megakaryoblastic leukemia., Competing Interests: Conflicts of interest The authors have no conflicts of interest to declare., (Copyright © 2023 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier España, S.L.U. All rights reserved.)
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- 2024
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24. Myeloid Proliferations of Down Syndrome
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McGhan, Lee J., Proytcheva, Maria A., Cheng, Liang, Series editor, George, Tracy I., editor, and Arber, Daniel A., editor
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- 2018
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25. Genomics analysis of leukaemia predisposition in X‐linked agammaglobulinaemia.
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Nishimura, Akira, Naruto, Takuya, Miyamoto, Satoshi, Grigg, Andrew, Bosco, Julian J., Hoshino, Akihiro, Amano, Keishiro, Iwamoto, Shotaro, Hirayama, Masahiro, Migita, Masahiro, Ohara, Osamu, Takagi, Masatoshi, Morio, Tomohiro, Zelm, Menno C., and Kanegane, Hirokazu
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AGAMMAGLOBULINEMIA , *LEUKEMIA , *TUMOR suppressor genes , *GENOMICS , *B cell differentiation , *CHRONIC leukemia , *HEREDITARY nonpolyposis colorectal cancer - Abstract
BCP-ALL of the XLA patients did not show a distinctive methylation profile. X-linked agammaglobulinemia, Bruton's tyrosine kinase, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, tumor suppressor Keywords: X-linked agammaglobulinemia; Bruton's tyrosine kinase; acute lymphoblastic leukemia; acute megakaryoblastic leukemia; tumor suppressor EN X-linked agammaglobulinemia Bruton's tyrosine kinase acute lymphoblastic leukemia acute megakaryoblastic leukemia tumor suppressor 1277 1281 5 06/18/21 20210615 NES 210615 X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by pathogenic variants in I Bruton's tyrosine kinase i ( I BTK i ). Future studies in which many patients with XLA with leukemia are enrolled may be able to clarify the more detailed characteristics of leukaemic cells in XLA. [Extracted from the article]
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- 2021
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26. Clinical features of 35 Down syndrome patients with transient abnormal myelopoiesis at a single institution.
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Yamato, Genki, Park, Myoung-ja, Sotomatsu, Manabu, Kaburagi, Taeko, Maruyama, Kenichi, Kobayashi, Tomio, Nishi, Akira, Sameshima, Kiyoko, Ohki, Kentaro, and Hayashi, Yasuhide
- Abstract
Transient abnormal myelopoiesis (TAM) is a unique clonal myeloproliferation characterized by immature megakaryoblasts that occurs in 5–10% of neonates with Down syndrome (DS). Although TAM regresses spontaneously in most patients, approximately 20% of TAM cases result in early death, and approximately 20% of survivors develop acute megakaryoblastic leukemia (AMKL). We retrospectively reviewed records of 35 DS patients with TAM to determine the correlation between clinical characteristics and blast percentage. Thirteen of the 35 patients were classified as low blast percentage TAM (LBP-TAM), defined as TAM with a peak peripheral blast percentage ≤ 10%. Although no patient with LBP-TAM experienced systemic edema, disseminated intravascular coagulation, or early death, eight patients had elevated direct bilirubin levels (> 2 mg/dl) and one developed AMKL. All patients with LBP-TAM had serum markers of liver fibrosis that exceeded the normal limits, and two patients underwent liver biopsy to clarify the etiology of pathological jaundice. Taken together, our results suggest that patients with LBP-TAM may be at risk of liver fibrosis and liver failure, similarly to patients with classical TAM. Although these patients generally have a good prognosis, they should be carefully monitored for potential development of liver disease and leukemia. [ABSTRACT FROM AUTHOR]
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- 2021
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27. Acute Megakaryoblastic Leukemia
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Bourquin, Jean-Pierre, Izraeli, Shai, and Schwab, Manfred, editor
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- 2017
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28. Molecular Mechanisms of the Genetic Predisposition to Acute Megakaryoblastic Leukemia in Infants With Down Syndrome.
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Grimm, Juliane, Heckl, Dirk, and Klusmann, Jan-Henning
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DOWN syndrome ,ACUTE leukemia ,MYELOID leukemia ,INFANTS ,SOMATIC mutation ,COHESINS ,PAROXYSMAL hemoglobinuria - Abstract
Individuals with Down syndrome are genetically predisposed to developing acute megakaryoblastic leukemia. This myeloid leukemia associated with Down syndrome (ML–DS) demonstrates a model of step-wise leukemogenesis with perturbed hematopoiesis already presenting in utero , facilitating the acquisition of additional driver mutations such as truncating GATA1 variants, which are pathognomonic to the disease. Consequently, the affected individuals suffer from a transient abnormal myelopoiesis (TAM)—a pre-leukemic state preceding the progression to ML–DS. In our review, we focus on the molecular mechanisms of the different steps of clonal evolution in Down syndrome leukemogenesis, and aim to provide a comprehensive view on the complex interplay between gene dosage imbalances, GATA1 mutations and somatic mutations affecting JAK-STAT signaling, the cohesin complex and epigenetic regulators. [ABSTRACT FROM AUTHOR]
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- 2021
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29. Blast cells in acute megakaryoblastic leukaemia with Down syndrome are characterized by low CLEC12A expression.
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Matsuo, Hidemasa, Wakita, Tomohiro, Hiramatsu, Hidefumi, Ohmori, Katsuyuki, Kodama, Kumi, Nakatani, Kana, Kamikubo, Yasuhiko, Iwamoto, Shotaro, Kondo, Tadakazu, Takaori‐Kondo, Akifumi, Takita, Junko, Tomizawa, Daisuke, Taga, Takashi, and Adachi, Souichi
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- *
ACUTE leukemia , *DOWN syndrome , *ACUTE myeloid leukemia , *CHILD patients - Abstract
Keywords: acute megakaryoblastic leukemia; Down syndrome; CLEC12A; TIM3; CD96 EN acute megakaryoblastic leukemia Down syndrome CLEC12A TIM3 CD96 e7 e11 5 12/21/20 20210101 NES 210101 Acute myeloid leukaemia (AML) is a genetically and clinically heterogeneous disease, characterized by expansion of undifferentiated myeloid precursor cells.1 Despite an increased understanding of the biology and therapeutic advances, the outcomes of AML patients remain unsatisfactory. The average CLEC12A-positive cell rate was significantly lower in FAB-M7 cases (10-8%) than that in non-FAB-M7 cases (91-8%, I P i = 2.8E-20; Fig 1C); however, the average TIM3-positive cell rate did not differ significantly between the two groups (67-5% vs. 62-1%, respectively, I P i = 0-66). The average CD96-positive cell rate was also significantly lower in samples from FAB-M7 patients (20-7%) than in those from non-FAB-M7 patients (59-5%, I P i = 0-0002). [Extracted from the article]
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- 2021
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30. Gene mutation landscape of a rare patient with acute megakaryoblastic leukemia after treatment of intracranial germ cell tumor
- Abstract
IntroductionIt was first reported that germ cell tumor patients suffer from hematologic malignancies 37 years ago. Since then, the number of relevant reports has increased each year, with most cases being mediastinal germ cell tumor. Theories have been proposed to explain this phenomenon, including a shared origin of progenitor cells, the effects of treatment, and independent development. However, up to now, no widely accepted explanation exists. The case with acute megakaryoblastic leukemia and intracranial germ cell tumor has never been reported before and the association is far less known. MethodsWe used whole exome sequencing and gene mutation analysis to study the relationship between intracranial germ cell tumor and acute megakaryoblastic leukemia of our patient. ResultsWe report a patient who developed acute megakaryoblastic leukemia after treatment for an intracranial germ cell tumor. Through whole exome sequencing and gene mutation analysis, we identified that both tumors shared the same mutation genes and mutation sites, suggesting they originated from the same progenitor cells and differentiated in the later stage. DiscussionOur findings provide the first evidence supporting the theory that acute megakaryoblastic leukemia and intracranial germ cell tumor has the same progenitor cells.
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- 2023
31. Skin Manifestations of Micafungin Breakthrough Disseminated Trichosporonosis in Acute Megakaryoblastic Leukemia.
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Matsumoto Y, Arakawa S, Sadahira K, Sato T, Yamazaki K, and Nishimoto S
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- Male, Humans, Micafungin, Antifungal Agents therapeutic use, Voriconazole, Erythema complications, Erythema drug therapy, Trichosporonosis diagnosis, Trichosporonosis drug therapy, Trichosporonosis microbiology, Leukemia, Megakaryoblastic, Acute complications, Leukemia, Megakaryoblastic, Acute drug therapy, Trichosporon, Hematologic Neoplasms complications, Hematologic Neoplasms drug therapy
- Abstract
Disseminated trichosporonosis is a rare fungal infection whose risk factors are hematological malignancies and neutropenia. Recently, breakthrough Trichosporon infections after administration of micafungin, the first-line systemic antifungal agent in compromised hosts, have been widely recognized. A man in his seventies about 1 month into chemotherapy for acute megakaryoblastic leukemia presented with a worsening fever and dyspnea. The patient was being administered with empirical micafungin therapy for suspected candidiasis. As the symptoms progressed, scattered erythema appeared on the trunk, some with a dark red vesicle at the center. Blood cultures identified Trichosporon asahii, as did the specimen of the skin biopsy. On the basis also of the presence of pneumonia on chest computed tomography, we confirmed the diagnosis of disseminated trichosporonosis and changed the antifungal agent from micafungin to voriconazole. Blood culture turned out to be negative 1 month after administrating voriconazole. However, the patient died of the leukemia. Our review of previous reports on cutaneous manifestations of disseminated trichosporonosis revealed that despite their morphological diversity, erythema with a red papule or vesicle at the center, implying necrosis, was also observed in previous cases. Our case report suggests that dermatologists should be aware of skin manifestations of disseminated trichosporonosis after micafungin administration, especially in cases of hematological malignancies.
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- 2024
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32. Effects of metformin on proliferation and apoptosis of human megakaryoblastic Dami and MEG-01 cells
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Xue Liang, Peiyan Kong, Jin Wang, Yulin Xu, Chunfang Gao, and Guozhen Guo
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Acute megakaryoblastic leukemia ,Metformin ,Dami ,MEG-01 ,Apoptosis ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Metformin has received increasing attention for its potential anticancer activity against certain human leukemia cells, but its effects on human megakaryoblastic cells are unclear. This study aimed to investigate the effects of metformin on proliferation and apoptosis of human megakaryoblastic cells (Dami and MEG-01) and the underlying molecular mechanisms. CCK8 assay was employed to measure cell proliferation. Flow cytometry was adopted to detect cell apoptosis. Western blot was further employed to measure apoptosis-related proteins. In Dami and MEG-01 cells, metformin significantly inhibited proliferation and promoted apoptosis in a dose- and time-dependent manner, and metformin (4 mM) was selected for subsequent experiments. Metformin inhibited ERK1/2, JNK, and PI3K/Akt, but activated p38 pathway in these two cells. Moreover, inhibition of ERK1/2, JNK or PI3K/Akt pathway alone induced cell apoptosis compared to the control group. The combination of specific inhibitors of ERK1/2, JNK or PI3K/Akt pathway and metformin further promoted cell apoptosis and the up-regulation of p21, Bax, Bad, cleaved caspase-3 and -9 as well as the down-regulation of Bcl-2 mediated by metformin alone, but inhibition of p38 pathway exhibited the opposite results. These findings support the possibility of metformin treatment as a new therapeutic strategy against acute megakaryoblastic leukemia (AMKL).
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- 2017
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33. GATA1 Gene Polymorphisms in Down Syndrome Patients
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Kherlen Ponkhoon, Uranchimeg Bayarmagnai, Sarantuya Jav, and Munkhtuya Tumurkhuu
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down syndrome ,gata1 transcription factor ,acute megakaryoblastic leukemia ,single nucleotide polymorphism ,Medicine ,Medicine (General) ,R5-920 - Abstract
Objectives: Down syndrome (DS) patients have a 500 fold higher possibility of developing acute megakaryoblastic leukemia (AMKL), compared with the general population. GATA1 mutations, acquired in the early prenatal stages, contributes to leukemogenesis in AMKL and has been the explanation for the cause of early hematopoietic disorders. The aim of this study was to investigate the influence of GATA1 gene polymorphisms in patients with DS. Methods: Thirty-nine DS patients, aged ≤ 4 years, were recruited into the study. GATA1 gene polymorphisms were identified by unidirectional deep sequencing. Results: GATA1 gene polymorphisms were identified in four patients: proband-11 had GATA1 gene polymorphism, NP_002040.1:p.His71Arg (rs374300356); proband-17 had NP_002040.1:p. Tyr69Cys; proband-19 had NP_002040.1:p.Lys100Arg; and proband-20 had NP_002040.1:p. Tyr69Cys. Analyzing these GATA1 gene polymorphisms with 14 different software programs to evaluate its pathogenicity showed that NP_002040.1:p.His71Arg had damaging effects on GATA1 gene function. Conclusion: We identified four GATA1 gene polymorphisms in this cohort of 39 patients. The polymorphism identified in proband-11 (NP_002040.1:p.His71Arg) has possible damaging effects on gene regulation, and thus, we recommend routine clinical examination in this patient.
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- 2017
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34. Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene
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Riccardo Masetti, Salvatore Nicola Bertuccio, Annalisa Astolfi, Francesca Chiarini, Annalisa Lonetti, Valentina Indio, Matilde De Luca, Jessica Bandini, Salvatore Serravalle, Monica Franzoni, Martina Pigazzi, Alberto Maria Martelli, Giuseppe Basso, Franco Locatelli, and Andrea Pession
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Acute myeloid leukemia ,Acute megakaryoblastic leukemia ,CBFA2T3-GLIS2 ,GANT61 ,Hedgehog pathway ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. Methods We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression profile. Results As compared to AML cells without GLIS2 fusion, GANT61 exposure resulted in higher sensitivity of both cell lines and primary AML cells carrying CBFA2T3-GLIS2 to undergo apoptosis and G1 cell cycle arrest. Remarkably, gene expression studies demonstrated downregulation of GLIS2-specific signature genes in both treated cell lines and primary cells, in comparison with untreated cells. Moreover, chromatin immunoprecipitation analysis revealed direct regulation by GLIS2 chimeric protein of DNMT1 and DNMT3B, two genes implicated in important epigenetic functions. Conclusions Our findings indicate that the GLI inhibitor GANT61 may be used to specifically target the CBFA2T3-GLIS2 fusion gene in pediatric AML.
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- 2017
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35. Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype
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Vijay G. Sankaran, Deepa Bhojwani, C. Michel Zwaan, Nik F Nik-Abdul-Rashid, Josefine Palle, Jeffrey M Verboon, Stephanie DiTroia, Klas Raaschou-Jensen, Charlotte Guldborg Nyvold, Alan B. Cantor, Katherine R. Chao, Ronald M Kline, Henrik Hasle, Eigil Kjeldsen, and Pediatrics
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Male ,Down syndrome ,Immunology ,Trisomy ,Biochemistry ,Germline ,Acute megakaryoblastic leukemia ,Leukemia, Megakaryoblastic, Acute ,hemic and lymphatic diseases ,medicine ,Humans ,GATA1 Transcription Factor ,Germ-Line Mutation ,Myeloid Neoplasia ,business.industry ,Myeloid leukemia ,GATA1 ,Cell Biology ,Hematology ,medicine.disease ,Leukemia ,Phenotype ,Leukemia, Myeloid ,Child, Preschool ,Tetrasomy ,Mutation ,Cancer research ,Down Syndrome ,business - Abstract
Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.
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- 2022
36. The changing scenario of non-Down syndrome acute megakaryoblastic leukemia in children.
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Masetti, Riccardo, Guidi, Vanessa, Ronchini, Laura, Bertuccio, Nicola Salvatore, Locatelli, Franco, and Pession, Andrea
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- *
ACUTE leukemia , *GENETIC disorders , *BIOMARKERS , *THERAPEUTICS , *HEMATOPOIETIC stem cell transplantation - Abstract
• Recent discovery of novel genetic lesions characterizing non-DS-AMKL. • A more refined genetic risk-assessment allowed a tailored treatment approach. • High-risk group: NUP98-KDM5 A, CBFA2T3-GLIS2, KMT2A -rearrangements and monosomy 7. • HSCT in first complete remission to avoid recurrence in high-risk non-DS-AMKL. • Intensive chemotherapy approach in standard-risk group, HSCT in case of poor response. Pediatric non-Down-syndrome acute megakaryoblastic leukemia (non-DS-AMKL) is a heterogeneous subtype of leukemia that has historically been associated with poor prognosis. Until the advent of large-scale genomic sequencing, the management of patients with non-DS-AMKL was very difficult due to the absence of reliable biological prognostic markers. The sequencing of large cohort of pediatric non-DS-AMKL samples led to the discovery of novel genetic aberrations, including high-frequency fusions, such as CBFA2T3-GLIS2 and NUP98-KDM5 A , as well as less frequent aberrations, such as HOX rearrangements. These new insights into the genetic landscape of pediatric non-DS-AMKL has allowed refining the risk-group stratification, leading to important changes in the prognostic scenario of these patients. This review summarizes the most important molecular pathogenic mechanisms of pediatric non-DS-AMKL. A critical discussion on how novel genetic abnormalities have refined the risk profile assessment and changed the management of these patients in clinical practice is also provided. [ABSTRACT FROM AUTHOR]
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- 2019
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37. A Case of Pediatric Acute Megakaryoblastic Leukemia without Down Syndrome where Evidence of Cytoplasmic Antigen by Flow Cytometry Contributed to the Diagnosis
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Akihiro, Kondo, Kayoko, Seo, Akihiro, Takeuchi, Ryosuke, Mori, Mari, Nishitani, Hirofumi, Yagi, and Hiroyuki, Kiuchi
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non-DS-AMKL ,493.931 ,フローサイトメトリー ,platelet-related antigens ,492.1 ,急性巨核芽球性白血病| 小児非Down症急性巨核芽球性白血病 ,flow cytometry ,492.17 ,acute megakaryoblastic leukemia ,血小板関連抗原 - Abstract
非Down症児における急性巨核芽球性白血病 (AMKL) の発症は稀であり, 予後不良である. 症例は1歳4ヶ月の女児. 繰り返す発熱を主訴に他院にて治療されていたが, 末梢血中に芽球が出現したため, 香川大学医学部附属病院小児科に紹介入院となった. 血液検査の結果, 著明な白血球増多と貧血を呈しており, 芽球を2.0%認めたことから, 白血病の可能性を考慮し, 骨髄検査が行われた. 骨髄は高度過形成で芽球様細胞が78.8%認められた. 芽球様細胞は大小不同があり, 細胞質は好塩基性が強く, 辺縁はときにbleb様突起などの不整があり, ミエロペルオキシダーゼ (MPO) 染色は陰性であった. フローサイトメトリー (FCM) による細胞表面抗原はCD33, CD56, CD61, CD117陽性で, CD9, CD34, CD36, CD41, CD110などは陰性を示し, 細胞質内抗原ではTdT, CD3, CD79a, MPOがいずれも陰性であった. FCMの結果からAMKLの可能性を疑い, 細胞質内のCD41とCD61を追加で染色したところ共に陽性を示した. さらに染色体検査の結果が正常女性核型であったことから, 上記の所見と合わせて小児非Down症AMKL (non-DS-AMKL) と診断された. AMKLの巨核芽球は血小板関連抗原 (CD41, CD61, CD42b) のうち一つ以上が陽性を示すとされる. 本症例は形態的にAMKLの特徴を一部有し, 細胞表面のCD61が陽性でAMKLの条件を満たしたが, 非Down症児であることから, 芽球に付着した血小板による偽陽性の可能性を否定できず診断に苦慮した. しかし, 特異性が高いとされる細胞質内CD41, CD61の発現を証明できたことが確定診断をする上で根拠の一つとなり, FCMによる細胞内染色の重要性を再認識した症例であった. Acute megakaryoblastic leukemia (AMKL) in children without Down syndrome is rare and has a poor prognosis. A 16-month-old female, who was treated at another hospital with repeated fever, was referred to the Department of Pediatrics, Kagawa University Hospital, because of the appearance of blast cells in peripheral blood. A blood test showed marked leukocytosis and anemia, with 2.0% blast cells. Bone marrow was markedly hypercellular and 78.8% blast cells were observed. Blast cells were uneven in size, the cytoplasm was strongly basophilic, and the margins were sometimes irregular with bleb-like processes, and myeloperoxidase (MPO) staining was negative. Cell surface antigens by flow cytometry (FCM) were positive for CD33, CD56, CD61, and CD117, and negative for CD9, CD34, CD36, CD41, and CD110. The cytoplasmic antigens were negative for TdT, CD3, CD79a, and MPO. We suspected AMKL from FCM results, and when cytoplasmic CD41 and CD61 were additionally stained, both were positive. Furthermore, because the result of the chromosomal test showed a normal female karyotype, together with the above findings, a diagnosis of pediatric AMKL without Down syndrome (non-DS-AMKL) was made. AMKL megakaryoblasts are said to be positive for one or more of the platelet-related antigens (CD41, CD61, CD42b). This case had some morphological characteristics of AMKL, and the cells were positive for sCD61 which satisfied the conditions for AMKL. But because she was a non-Down syndrome child, the possibility of false positives due to platelets attached to blast cells could not be ruled out, making diagnosis difficult. However, the expression of cyCD41 and cyCD61, which are considered to be highly specific, was one of the criteria for making a definitive diagnosis. This case reaffirms the importance of intracellular staining by FCM.
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- 2022
38. The Comparative Sensitivity of Immunohistochemical Markers of Megakaryocytic Differentiation in Acute Megakaryoblastic Leukemia.
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Klairmont, Matthew M, Hoskoppal, Deepthi, Yadak, Nour, and Choi, John Kim
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- *
MEGAKARYOCYTE differentiation , *ACUTE myeloid leukemia , *IMMUNOHISTOCHEMISTRY - Abstract
Objectives: Immunohistochemistry (IHC) staining of core biopsy sections often plays an essential role in the diagnosis of acute megakaryoblastic leukemia (AMKL). The goal of this study was to define the relative sensitivities of commonly used stains for markers of megakaryocytic differentiation.Methods: The sensitivities of IHC stains for CD42b, CD61, and von Willebrand factor (vWF) were compared in 32 cases of pediatric AMKL.Results: The sensitivities of CD42b, CD61, and vWF were 90.6%, 78.1% and 62.5%, respectively. When CD42b and CD61 were used together, the combined sensitivity increased to 93.6%. There were no cases in which vWF was positive when both CD42b and CD61 were negative.Conclusions: CD42b can reliably be used as a solitary first-line marker for blasts of megakaryocytic lineage, whereas CD61 may be reserved for infrequent cases that are CD42b negative. There is no role for the routine use of vWF when CD42b and CD61 are available. [ABSTRACT FROM AUTHOR]- Published
- 2018
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39. RUNX1-EVI1 induces dysplastic hematopoiesis and acute leukemia of the megakaryocytic lineage in mice.
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Nakamura, Yuka, Ichikawa, Motoshi, Oda, Hideaki, Yamazaki, Ieharu, Sasaki, Ko, and Mitani, Kinuko
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ACUTE leukemia , *DYSPLASTIC nevus syndrome , *HEMATOPOIESIS , *LABORATORY mice , *CD31 antigen - Abstract
Graphical abstract Highlights • RUNX1-EVI1 expression resulted in two distinct phenotypes in mouse hematopoiesis. • One phenotype was dysplastic megakaryopoiesis with tendency to thrombocytosis. • The other was megakaryoblastic leukemia with CD41 and CD31 expression. • Primitive hematopoietic / endothelial genes were upregulated in leukemic cells. • This novel mouse model confirms the functions of RUNX1-EVI1 on leukemogenesis. Abstract The RUNX1-EVI1 gene generated by the t(3;21) translocation encodes a chimeric transcription factor and is a causative gene in the development of de novo acute megakaryoblastic leukemia and leukemic transformation of hematopoietic stem cell tumors. Heterozygous RUNX1-EVI1 knock-in mice die in utero due to hemorrhage in the central nervous system and spinal cord and complete abolishment of definitive hematopoiesis in the fetal liver. On the other hand, the chimeric knock-in mouse develops acute megakaryoblastic leukemia. We created another mouse model of RUNX1-EVI1 using transplantation of retrovirus-infected bone marrow cells. Some mice transplanted with RUNX1-EVI1 -expressing bone marrow cells developed acute megakaryoblastic leukemia within eight months, and the other non-leukemic mice showed thrombocytosis at around a year. In the non-leukemic mice, dysplastic megakaryocytes proliferated in the bone marrow and frequently infiltrated into the spleen, which was not associated with marrow fibrosis. In the leukemic mice, their tumor cells were positive for c-kit and CD41, and negative for TER119. Although they were negative for platelet peroxidase in the electron microscopic analysis, they had multiple centrioles in the cytoplasm, which are characteristic of megakaryocytes that undergo endomitosis. The leukemic cells were serially transplantable, and gene-expression analyses using quantitative RT-PCR arrays revealed that they showed significantly elevated expression of stem cell, primitive hematopoietic cell and endothelial cell-related genes compared with normal bone marrow cells. All these data suggested that RUNX1-EVI1 caused dysplastic hematopoiesis or leukemia of the megakaryocytic lineage and endowed gene expression profiles distinctive of immature hematopoietic cells. [ABSTRACT FROM AUTHOR]
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- 2018
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40. CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to navitoclax.
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Neault, Mathieu, Lebert-Ghali, Charles-Étienne, Fournier, Marilaine, Capdevielle, Caroline, Garfinkle, Elizabeth A.R., Obermayer, Alyssa, Cotton, Anitria, Boulay, Karine, Sawchyn, Christina, St-Amand, Sarah, Nguyen, Kamy H., Assaf, Béatrice, Mercier, François E., Delisle, Jean-Sébastien, Drobetsky, Elliot A., Hulea, Laura, Shaw, Timothy I., Zuber, Johannes, Gruber, Tanja A., and Melichar, Heather J.
- Abstract
Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive blood cancer associated with poor therapeutic response and high mortality. Here we describe the development of CBFA2T3-GLIS2-driven mouse models of AMKL that recapitulate the phenotypic and transcriptional signatures of the human disease. We show that an activating Ras mutation that occurs in human AMKL increases the penetrance and decreases the latency of CBF2AT3-GLIS2-driven AMKL. CBFA2T3-GLIS2 and GLIS2 modulate similar transcriptional networks. We identify the dominant oncogenic properties of GLIS2 that trigger AMKL in cooperation with oncogenic Ras. We find that both CBFA2T3-GLIS2 and GLIS2 alter the expression of a number of BH3-only proteins, causing AMKL cell sensitivity to the BCL2 inhibitor navitoclax both in vitro and in vivo , suggesting a potential therapeutic option for pediatric patients suffering from CBFA2T3-GLIS2-driven AMKL. [Display omitted] • Transplantation of CBFA2T3-GLIS2-expressing fetal liver cells causes AMKL in mice • GLIS2 cooperates with activated Nras to promote the development of AMKL • CBFA2T3-GLIS2 and GLIS2 alter the expression of BCL2 family members • CBFA2T3-GLIS2-dependent AMKL is sensitive to the BCL2 inhibitor navitoclax Using transcriptomic characterization of CBFA2T3-GLIS2-driven acute megakaryoblastic leukemia (AMKL) derived from a mosaic murine model of the disease, Neault et al. show a critical contribution of GLIS2 and activated RAS in promoting AMKL. CBFA2T3-GLIS2 upregulates the expression of the anti-apoptotic protein BCL2, and CBFA2T3-GLIS2-positive AMKL cells are sensitive to navitoclax. [ABSTRACT FROM AUTHOR]
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- 2023
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41. Hypercalcemia and diffuse osteolytic lesions in a 45-year-old patient with myeloid sarcoma with megakaryocytic differentiation
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Aditya Goud, Abdelhai Abdelqader, Chanukya Dahagam, Ramez Jabaji, Pallavi Kumar, Albert Aboulafia, and Stephen Selinger
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myelofibrosis ,AML ,acute panmyelosis ,acute megakaryoblastic leukemia ,Internal medicine ,RC31-1245 - Abstract
Acute megakaryocytic leukemia is a rare form of acute myeloid leukemia that carries a poor prognosis. As most cases of osteolytic lesions are due to plasma cell and myeloid malignancies, maintaining a broad differential directly influences clinical course. We document a 45-year-old patient with progressive constitutional symptoms, osteolytic bone lesions in the setting of hypercalcemia, who developed acutely worsening pancytopenia. The diagnosis of myeloid sarcoma with megakaryocytic differentiation was made after obtaining tissue from osteolytic bone that stained strong for CD34. Immunohistochemical testing underscores the importance of how serologic and urine testing remains limited and can delay early diagnosis in this disease.
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- 2016
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42. A rare case of acute megakaryoblastic leukemia with orbital chloroma in a non-Down syndrome child
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Sahitya Koneru, Sandeep Jain, and Gauri Kapoor
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acute megakaryoblastic leukemia ,orbital chloroma ,hyperdiploidy ,immunophenotyping ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Acute megakaryoblastic leukemia (AMKL) is a rare disease accounting for 7%–10% of acute myeloid leukemia (AML) in children. It is uncommon in children without Down syndrome (DS). Orbital chloroma is usually associated with AML M2, M4, and M5. Herein, we report the case of a 22-month-old female who was diagnosed to have AMKL with orbital chloromas and without DS. Morphology and the initial panel of immunophenotyping were inconclusive and the presence of orbital chloromas added to the ambiguity. The presence of CD61 expression and marrow fibrosis supported by hyperdiploidy helped us clinch the diagnosis. Hence, comprehensive analysis of morphology, immunophenotyping, and cytogenetics is warranted to make an accurate diagnosis of AMKL.
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- 2017
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43. Hepatic myeloid sarcoma preceding acute megakaryoblastic leukemia with t(1;22) in an infant: Case report
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Zeynep Canan Özdemir, Ayşe Bozkurt Turhan, Beyhan Durak Aras, Berat Acu, and Özcan Bör
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Myeloid sarcoma ,Liver ,Infant ,Acute megakaryoblastic leukemia ,t(1 ,22) ,Pediatrics ,RJ1-570 - Abstract
Myeloid sarcoma (MS) is the tumor of immature myeloid cells involving extramedullary sites. Liver involvement of MS is rare in infant. Three months old female infant presented with hepatosplenomegaly and bicytopenia. Repeated bone marrow aspiration detected no blasts and flow cytometric analysis was normal. Abdominal magnetic resonance imaging revealed multiple nodular lesions in the liver. The biopsy results were consistent with MS. She presented with paleness and fever 8 months later. She had ongoing deep anemia, thrombocytopenia and hepatosplenomegaly. Bone marrow biopsy showed blast cell infiltration with 20% cells positive for CD61. The bone marrow karyotype investigation revealed complex quadruplet-translocation with the 46, X, t(X; 11; 22; 1) [15]/46, XX [1] karyotype. AML M7 was diagnosed and chemotherapy started. MS may occur as initial manifestation of AML with t(1;22) which is often associated with marrow fibrosis making sampling difficult. Hence cytogenetic analysis is of paramount importance in making an accurate diagnosis.
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- 2016
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44. Myelodysplasia and Myeloid Proliferations
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Singh, Zeba N., Gulley, Margaret L., and Mackinnon Jr, Alexander Craig, editor
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- 2012
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45. Salvage Cord Blood Transplantation for Sustained Remission of Acute Megakaryoblastic Leukemia That Relapsed Early after Myeloablative Transplantation
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Hideo Harigae, Junichi Kameoka, Noriko Fukuhara, Hisayuki Yokoyama, Yasushi Onishi, Satoshi Ichikawa, Tohru Fujiwara, Koichi Onodera, Kyoko Inokura, Kazuki Sakurai, and Kei Saito
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Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,Mediastinal germ cell tumor ,medicine.medical_treatment ,Case Report ,cord blood transplantation ,Hematopoietic stem cell transplantation ,030204 cardiovascular system & hematology ,mediastinal germ cell tumor ,03 medical and health sciences ,Acute megakaryoblastic leukemia ,0302 clinical medicine ,Refractory ,Leukemia, Megakaryoblastic, Acute ,Internal medicine ,Internal Medicine ,medicine ,Humans ,allogeneic hematopoietic stem cell transplantation ,Cord blood transplantation ,Salvage Therapy ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,General Medicine ,acute megakaryoblastic leukemia ,medicine.disease ,disseminated fusariosis ,Transplantation ,030211 gastroenterology & hepatology ,Cord Blood Stem Cell Transplantation ,Sustained remission ,business - Abstract
Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia accompanied by an aggressive clinical course and dismal prognosis. We herein report a case of AMKL preceded by mediastinal germ cell tumor that relapsed early after allogeneic hematopoietic stem cell transplantation with myeloablative conditioning but was successfully treated using salvage cord blood transplantation (CBT) with reduced-intensity conditioning. Although several serious complications developed, sustained remission with a favorable general condition was ultimately achieved. Although an optimal therapeutic strategy remains to be established, the graft-versus-leukemia effect of CBT may be promising, even for the treatment of refractory AMKL.
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- 2021
46. Acute Megakaryoblastic Leukemia
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Bourquin, Jean-Pierre, Izraeli, Shai, and Schwab, Manfred, editor
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- 2011
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47. Using Cytogenetic and Molecular Tests in Diagnostic Workups with the WHO Classification – 2008
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Whitcomb, Clarence C. and Crisan, Domnita, editor
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- 2011
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48. Classical and Molecular Cytogenetic Analysis of Hematolymphoid Disorders
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Micale, Mark A. and Crisan, Domnita, editor
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- 2011
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49. Update on the Molecular Pathology of Precursor Lymphoid Leukemias
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Lorsbach, Robert B. and Crisan, Domnita, editor
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- 2011
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50. Acute Megakaryoblastic Leukemia with t(1;22) Mimicking Neuroblastoma in an Infant
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Müge Gökçe, Selin Aytaç, Şule Ünal, İlhan Altan, Fatma Gümrük, and Mualla Çetin
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acute megakaryoblastic leukemia ,t(1 ,22) ,acute myeloid leukemia ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Acute megakaryoblastic leukemia (AMKL) with t(1;22) (p13;q13) is an extremely rare subtype of acute myeloid leukemia that is almost always described in infants. t(1;22) (p13;q13)-positive AMKL with extramedullary infiltration has been previously reported only once in the literature. Herein, we report a 3-month-old infant presenting with a pelvic mass and pancytopenia suggesting neuroblastoma. Bone marrow evaluation revealed t(1;22)-positive AMKL that responded well to a regimen containing high-dose cytarabine.
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- 2015
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