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51. Eltrombopag inhibits TET dioxygenase to contribute to hematopoietic stem cell expansion in aplastic anemia

Author

Guan, Yihong, Hasipek, Metis, Jiang, Dongxu, Tiwari, Anand D., Grabowski, Dale R., Pagliuca, Simona, Kongkiatkamon, Sunisa, Patel, Bhumika, Singh, Salendra, Parker, Yvonne, LaFramboise, Thomas, Lindner, Daniel, Sekeres, Mikkael A., Mian, Omar Y., Saunthararajah, Yogen, Maciejewski, Jaroslaw P., and Jha, Babal K.

Subjects
Eltrombopag -- Usage, Cell development (Biology) -- Genetic aspects -- Health aspects, Aplastic anemia -- Development and progression -- Drug therapy -- Genetic aspects, Hematopoietic stem cells -- Health aspects -- Genetic aspects, Health care industry
Abstract

Eltrombopag, an FDA-approved non-peptidyl thrombopoietin receptor agonist, is clinically used for the treatment of aplastic anemia, a disease characterized by hematopoietic stem cell failure and pancytopenia, to improve platelet counts and stem cell function. Eltrombopag treatment results in a durable trilineage hematopoietic expansion in patients. Some of the eltrombopag hematopoietic activity has been attributed to its off-target effects, including iron chelation properties. However, the mechanism of action for its full spectrum of clinical effects is still poorly understood. Here, we report that eltrombopag bound to the TET2 catalytic domain and inhibited its dioxygenase activity, which was independent of its role as an iron chelator. The DNA demethylating enzyme TET2, essential for hematopoietic stem cell differentiation and lineage commitment, is frequently mutated in myeloid malignancies. Eltrombopag treatment expanded TET2-proficient normal hematopoietic stem and progenitor cells, in part because of its ability to mimic loss of TET2 with simultaneous thrombopoietin receptor activation. On the contrary, TET inhibition in TET2 mutant malignant myeloid cells prevented neoplastic clonal evolution in vitro and in vivo. This mechanism of action may offer a restorative therapeutic index and provide a scientific rationale to treat selected patients with TET2 mutant-associated or TET deficiency-associated myeloid malignancies., Introduction Idiopathic aplastic anemia is characterized by immune-mediated hematopoietic progenitor and stem cell (HSPC) destruction, resulting in deficiencies across all hematopoietic lineages (1-3). Despite the therapeutic successes of immunosuppressive therapies, [...]

Published
2022
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53. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups

Author

Haase, Detlef, Stevenson, Kristen E., Neuberg, Donna, Maciejewski, Jaroslaw P., Nazha, Aziz, Sekeres, Mikkael A., Ebert, Benjamin L., Garcia-Manero, Guillermo, Haferlach, Claudia, Haferlach, Torsten, Kern, Wolfgang, Ogawa, Seishi, Nagata, Yasunobu, Yoshida, Kenichi, Graubert, Timothy A., Walter, Matthew J., List, Alan F., Komrokji, Rami S., Padron, Eric, Sallman, David, Papaemmanuil, Elli, Campbell, Peter J., Savona, Michael R., Seegmiller, Adam, Adès, Lionel, Fenaux, Pierre, Shih, Lee-Yung, Bowen, David, Groves, Michael J., Tauro, Sudhir, Fontenay, Michaela, Kosmider, Olivier, Bar-Natan, Michal, Steensma, David, Stone, Richard, Heuser, Michael, Thol, Felicitas, Cazzola, Mario, Malcovati, Luca, Karsan, Aly, Ganster, Christina, Hellström-Lindberg, Eva, Boultwood, Jacqueline, Pellagatti, Andrea, Santini, Valeria, Quek, Lynn, Vyas, Paresh, Tüchler, Heinz, Greenberg, Peter L., Bejar, Rafael, and for the International Working Group for MDS Molecular Prognostic Committee

Published
2019
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54. Molecular pathogenesis of disease progression in MLL-rearranged AML

Author

Kotani, Shinichi, Yoda, Akinori, Kon, Ayana, Kataoka, Keisuke, Ochi, Yotaro, Shiozawa, Yusuke, Hirsch, Cassandra, Takeda, June, Ueno, Hiroo, Yoshizato, Tetsuichi, Yoshida, Kenichi, Nakagawa, Masahiro M., Nannya, Yasuhito, Kakiuchi, Nobuyuki, Yamauchi, Takuji, Aoki, Kosuke, Shiraishi, Yuichi, Miyano, Satoru, Maeda, Takahiro, Maciejewski, Jaroslaw P., Takaori-Kondo, Akifumi, Ogawa, Seishi, and Makishima, Hideki

Published
2019
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55. Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia

Author

Guan, Yihong, Greenberg, Edward F., Hasipek, Metis, Chen, Shi, Liu, Xiaochen, Kerr, Cassandra M., Gackowski, Daniel, Zarakowska, Ewelina, Radivoyevitch, Tomas, Gu, Xiaorong, Willard, Belinda, Visconte, Valeria, Makishima, Hideki, Nazha, Aziz, Mukherji, Mridul, Sekeres, Mikkael A., Saunthararajah, Yogen, Oliński, Ryszard, Xu, Mingjiang, Maciejewski, Jaroslaw P., and Jha, Babal K.

Published
2020
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57. Influence of Killer Immunoglobulin-Like Receptors and Somatic Mutations on Transplant Outcomes in Acute Myeloid Leukemia

Author

Hong, Sanghee, Rybicki, Lisa, Zhang, Aiwen, Thomas, Dawn, Kerr, Cassandra M., Durrani, Jibran, Rainey, Magdalena A., Mian, Agrima, Behera, Tapas R., Carraway, Hetty E., Nazha, Aziz, Mukherjee, Sudipto, Advani, Anjali S., Patel, Bhumika, Kalaycio, Matt, Bolwell, Brian J., Hanna, Rabi, Gerds, Aaron T., Pohlman, Brad, Hamilton, Betty K., Sekeres, Mikkael A., Majhail, Navneet S., Maciejewski, Jaroslaw P., Askar, Medhat, and Sobecks, Ronald

Published
2021
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58. Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation

Author

Yoshizato, Tetsuichi, Nannya, Yasuhito, Atsuta, Yoshiko, Shiozawa, Yusuke, Iijima-Yamashita, Yuka, Yoshida, Kenichi, Shiraishi, Yuichi, Suzuki, Hiromichi, Nagata, Yasunobu, Sato, Yusuke, Kakiuchi, Nobuyuki, Matsuo, Keitaro, Onizuka, Makoto, Kataoka, Keisuke, Chiba, Kenichi, Tanaka, Hiroko, Ueno, Hiroo, Nakagawa, Masahiro M., Przychodzen, Bartlomiej, Haferlach, Claudia, Kern, Wolfgang, Aoki, Kosuke, Itonaga, Hidehiro, Kanda, Yoshinobu, Sekeres, Mikkael A., Maciejewski, Jaroslaw P., Haferlach, Torsten, Miyazaki, Yasushi, Horibe, Keizo, Sanada, Masashi, Miyano, Satoru, Makishima, Hideki, and Ogawa, Seishi

Published
2017
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60. Invariant patterns of clonal succession determine specific clinical features of myelodysplastic syndromes

Author

Nagata, Yasunobu, Makishima, Hideki, Kerr, Cassandra M., Przychodzen, Bartlomiej P., Aly, Mai, Goyal, Abhinav, Awada, Hassan, Asad, Mohammad Fahad, Kuzmanovic, Teodora, Suzuki, Hiromichi, Yoshizato, Tetsuichi, Yoshida, Kenichi, Chiba, Kenichi, Tanaka, Hiroko, Shiraishi, Yuichi, Miyano, Satoru, Mukherjee, Sudipto, LaFramboise, Thomas, Nazha, Aziz, Sekeres, Mikkael A., Radivoyevitch, Tomas, Haferlach, Torsten, Ogawa, Seishi, and Maciejewski, Jaroslaw P.

Published
2019
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62. Consequences of mutant TET2 on clonality and subclonal hierarchy

Author

Hirsch, Cassandra M., Nazha, Aziz, Kneen, Kassy, Abazeed, Mohamed E., Meggendorfer, Manja, Przychodzen, Bartlomiej P., Nadarajah, Niroshan, Adema, Vera, Nagata, Yasunobu, Goyal, Abhinav, Awada, Hassan, Asad, Mohammad Fahad, Visconte, Valeria, Guan, Yihong, Sekeres, Mikkael A., Olinski, Ryszard, Jha, Babal Kant, LaFramboise, Thomas, Radivoyevitch, Tomas, Haferlach, Torsten, and Maciejewski, Jaroslaw P.

Published
2018
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63. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents

Author

Wlodarski, Marcin W., Hirabayashi, Shinsuke, Pastor, Victor, Starý, Jan, Hasle, Henrik, Masetti, Riccardo, Dworzak, Michael, Schmugge, Markus, van den Heuvel-Eibrink, Marry, Ussowicz, Marek, De Moerloose, Barbara, Catala, Albert, Smith, Owen P., Sedlacek, Petr, Lankester, Arjan C., Zecca, Marco, Bordon, Victoria, Matthes-Martin, Susanne, Abrahamsson, Jonas, Kühl, Jörn Sven, Sykora, Karl-Walter, Albert, Michael H., Przychodzien, Bartlomiej, Maciejewski, Jaroslaw P., Schwarz, Stephan, Göhring, Gudrun, Schlegelberger, Brigitte, Cseh, Annámaria, Noellke, Peter, Yoshimi, Ayami, Locatelli, Franco, Baumann, Irith, Strahm, Brigitte, and Niemeyer, Charlotte M.

Published
2016
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69. Clonal evolution in aplastic anemia: failed tumor surveillance or maladaptive recovery?

Author

Gurnari, Carmelo, Pagliuca, Simona, and Maciejewski, Jaroslaw P.

Subjects
APLASTIC anemia, NUCLEOTIDE sequencing, BONE marrow, HLA histocompatibility antigens, TUMORS, PAROXYSMAL hemoglobinuria
Abstract

Clonal evolution to secondary paroxysmal nocturnal hemoglobinuria (PNH) or myeloid neoplasia (MN) represents one of the long-term complications of patients with aplastic anemia (AA). The recent evidence in the field of immunology and the application of next-generation sequencing have shed light on the molecular underpinnings of these clonal complications, revealing clinical and molecular risk factors as well as potential immunological players. Particularly, whether MN evolution represents a failed tumor surveillance or a maladaptive recovery is still a matter of controversy in the field of bone marrow failure syndromes. However, recent studies have explored the precise dynamics of the immune-molecular forces governing such processes over time, generating knowledge useful for potential early therapeutic strategies. In this review, we will discuss the immune pathophysiology of AA and the emergence of clonal hematopoiesis with regard to the adaptive and maladaptive mechanisms at the basis of secondary evolution trajectories operating under the immune pressure. [ABSTRACT FROM AUTHOR]

Published
2023
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70. Relationship of paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size to disease burden and risk of major vascular events in untreated patients: results from the International PNH Registry.

Author

Dingli, David, Maciejewski, Jaroslaw P., Larratt, Loree, Go, Ronald S., Höchsmann, Britta, Zu, Ke, Gustovic, Philippe, and Kulagin, Alexander D.

Subjects
*PAROXYSMAL hemoglobinuria, *SOMATIC mutation, *FATIGUE (Physiology), *BLOOD proteins, *LACTATE dehydrogenase, *BLOOD cells
Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is caused by acquired gene mutations resulting in deficiency of glycosylphosphatidylinositol (GPI)–anchored complement regulatory proteins on the surface of blood cells, leading to terminal complement–mediated intravascular hemolysis and increased risk of major adverse vascular events (MAVEs). Using data from the International PNH Registry, this study investigated the relationship between the proportion of GPI-deficient granulocytes at PNH onset and (1) the risk for MAVEs (including thrombotic events [TEs]) and (2) the following parameters at last follow-up: high disease activity (HDA); lactate dehydrogenase (LDH) ratio; fatigue; abdominal pain; and rates of overall MAVEs and TEs. A total of 2813 patients untreated at enrollment were included and stratified by clone size at PNH disease onset (baseline). At last follow-up, higher proportion of GPI-deficient granulocytes (≤ 5% vs. > 30% clone size) at baseline was associated with significantly increased HDA incidence (14% vs. 77%), mean LDH ratio (1.3 vs. 4.7 × upper limit of normal), and rates of MAVEs 1.5 vs. 2.9 per 100 person-years) and TEs (0.9 vs. 2.0 per 100 person-years). Fatigue was evident in 71 to 76% of patients regardless of clone size. Abdominal pain was more frequently reported with clone size > 30%. A larger clone size at baseline appears to indicate a greater disease burden and risk of TEs and MAVEs and may inform decision making among physicians managing PNH patients at risk of experiencing TEs or other MAVEs. ClinicalTrials.gov ID: NCT01374360. [ABSTRACT FROM AUTHOR]

Published
2023
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74. STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients

Author

Jerez, Andres, Clemente, Michael J., Makishima, Hideki, Rajala, Hanna, Gómez-Seguí, Ines, Olson, Thomas, McGraw, Kathy, Przychodzen, Bartlomiej, Kulasekararaj, Austin, Afable, Manuel, Husseinzadeh, Holleh D., Hosono, Naoko, LeBlanc, Francis, Lagström, Sonja, Zhang, Dan, Ellonen, Pekka, Tichelli, André, Nissen, Catherine, Lichtin, Alan E., Wodnar-Filipowicz, Aleksandra, Mufti, Ghulam J., List, Alan F., Mustjoki, Satu, Loughran, Thomas P., Jr, and Maciejewski, Jaroslaw P.

Published
2013
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76. Targeting IRAK1 as a Therapeutic Approach for Myelodysplastic Syndrome

Author

Rhyasen, Garrett W., Bolanos, Lyndsey, Fang, Jing, Jerez, Andres, Wunderlich, Mark, Rigolino, Carmela, Mathews, Lesley, Ferrer, Marc, Southall, Noel, Guha, Rajarshi, Keller, Jonathan, Thomas, Craig, Beverly, Levi J., Cortelezzi, Agostino, Oliva, Esther N., Cuzzola, Maria, Maciejewski, Jaroslaw P., Mulloy, James C., and Starczynowski, Daniel T.

Published
2013
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78. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia

Author

Rajala, Hanna L.M., Eldfors, Samuli, Kuusanmäki, Heikki, van Adrichem, Arjan J., Olson, Thomas, Lagström, Sonja, Andersson, Emma I., Jerez, Andres, Clemente, Michael J., Yan, Yiyi, Zhang, Dan, Awwad, Andy, Ellonen, Pekka, Kallioniemi, Olli, Wennerberg, Krister, Porkka, Kimmo, Maciejewski, Jaroslaw P., Loughran, Thomas P., Jr, Heckman, Caroline, and Mustjoki, Satu

Published
2013
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80. Mutations in G protein β subunits promote transformation and kinase inhibitor resistance

Author

Yoda, Akinori, Adelmant, Guillaume, Tamburini, Jerome, Chapuy, Bjoern, Shindoh, Nobuaki, Yoda, Yuka, Weigert, Oliver, Kopp, Nadja, Wu, Shuo-Chieh, Kim, Sunhee S., Liu, Huiyun, Tivey, Trevor, Christie, Amanda L., Elpek, Kutlu G., Card, Joseph, Gritsman, Kira, Gotlib, Jason, Deininger, Michael W., Makishima, Hideki, Turley, Shannon J., Javidi-Sharifi, Nathalie, Maciejewski, Jaroslaw P., Jaiswal, Siddhartha, Ebert, Benjamin L., Rodig, Scott J., Tyner, Jeffrey W., Marto, Jarrod A., Weinstock, David M., and Lane, Andrew A.

Subjects
Gene mutations -- Physiological aspects -- Research, Tumors -- Risk factors -- Genetic aspects -- Research, G proteins -- Physiological aspects -- Genetic aspects -- Research, Biological sciences, Health
Abstract

Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers (1), but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβg dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling., Numerous somatic mutations are present in less than 5% of cases across multiple tumor types. To extensively catalog mutations in these 'long-tail' genes (2) will require sequencing thousands of additional [...]

Published
2015

81. New approaches to idiopathic neutropenia in the era of clonal hematopoiesis.

Author

Ogbue, Olisaemeka D., Kewan, Tariq, Bahaj, Waled S., Gurnari, Carmelo, Visconte, Valeria, and Maciejewski, Jaroslaw P.

Subjects
MONOCLONAL gammopathies, HEMATOPOIESIS, NEUTROPENIA, LYMPHOCYTIC leukemia, T cells, RARE diseases
Abstract

Isolated chronic idiopathic neutropenia (CIN) is a rare disease with multiple contributing etiologies that must be ruled out before establishing a diagnosis. We studied clinical and molecular data of 238 consecutive adult patients with CIN. Autoimmune neutropenia was present in 28% of our cohort. In contrast, T cell-mediated neutropenia was the main underlying pathological mechanism among patients with T cell expansions, such as T-cell large granular lymphocytic leukemia (T-LGL) and T cell clonopathy of undetermined significance, found in 37% and 8% of cases, respectively. Patients with neutropenia also had hypogammaglobulinemia (6%) and/or monoclonal gammopathy of undetermined significance (5%). NGS application has further broadened the spectrum of causes of CIN by including manifestations of clonal hematopoiesis, present in 12% of cases. TET2 (3%), TP53 (2%), and IDH1/IDH2 (2%) mutations were the most commonly found and were enriched in cases with T-LGL. We show that these clinico-molecular associations can be simultaneously present, complicating a proper diagnostic distinction within the broader entity of seemingly idiopathic neutropenia of autoimmune origin. Identification of etiologic culprits may also guide rational selection of therapies. [ABSTRACT FROM AUTHOR]

Published
2023
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82. Are the current guidelines for identification of myelodysplastic syndrome with germline predisposition strong enough?

Author

Calvete, Oriol, Mestre, Julia, Durmaz, Arda, Gurnari, Carmelo, Maciejewski, Jaroslaw P., and Solé, Francesc

Subjects
MYELODYSPLASTIC syndromes, GERM cells, SINGLE nucleotide polymorphisms, HEREDITARY nonpolyposis colorectal cancer, HEMATOPOIETIC stem cell transplantation
Abstract

Although the higher the VAF is, the higher the possibility to find a germline variant, overlapping VAFs between somatic and germline variants are expected in MDS patients (Figure 1B,C). Such publications described that deleterious germline predisposition variants are shared by MDS patients of all ages[[11], [16]] in contrast to the current guidelines, which consider that MDS arising from germline predisposition occurs only in younger patients. Keywords: current guidelines; genetic predisposition; germline variants; myelodysplastic syndrome (MDS); Variant allele frequency (VAF) EN current guidelines genetic predisposition germline variants myelodysplastic syndrome (MDS) Variant allele frequency (VAF) e5 e11 7 03/30/23 20230401 NES 230401 Myelodysplastic syndrome (MDS) is a malignant condition characterized by ineffective haematopoiesis that typically presents in older adults (73.5 years on average) with a stepwise process driven by the acquisition of age-related somatic mutations. [Extracted from the article]

Published
2023
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83. SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes

Author

Visconte, Valeria, Rogers, Heesun J., Singh, Jarnail, Barnard, John, Bupathi, Manoj, Traina, Fabiola, McMahon, James, Makishima, Hideki, Szpurka, Hadrian, Jankowska, Anna, Jerez, Andres, Sekeres, Mikkael A., Saunthararajah, Yogen, Advani, Anjali S., Copelan, Edward, Koseki, Haruhiko, Isono, Kyoichi, Padgett, Richard A., Osman, Sami, Koide, Kazunori, O'Keefe, Christine, Maciejewski, Jaroslaw P., and Tiu, Ramon V.

Published
2012
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84. STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia

Author

Jerez, Andres, Clemente, Michael J., Makishima, Hideki, Koskela, Hanna, LeBlanc, Francis, Peng Ng, Kwok, Olson, Thomas, Przychodzen, Bartlomiej, Afable, Manuel, Gomez-Segui, Ines, Guinta, Kathryn, Durkin, Lisa, Hsi, Eric D., McGraw, Kathy, Zhang, Dan, Wlodarski, Marcin W., Porkka, Kimmo, Sekeres, Mikkael A., List, Alan, Mustjoki, Satu, Loughran, Thomas P., and Maciejewski, Jaroslaw P.

Published
2012
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86. Loss of heterozygosity in 7q myeloid disorders: clinical associations and genomic pathogenesis

Author

Jerez, Andres, Sugimoto, Yuka, Makishima, Hideki, Verma, Amit, Jankowska, Anna M., Przychodzen, Bartlomiej, Visconte, Valeria, Tiu, Ramon V., O'Keefe, Christine L., Mohamedali, Azim M., Kulasekararaj, Austin G., Pellagatti, Andrea, McGraw, Kathy, Muramatsu, Hideki, Moliterno, Alison R., Sekeres, Mikkael A., McDevitt, Michael A., Kojima, Seiji, List, Alan, Boultwood, Jacqueline, Mufti, Ghulam J., and Maciejewski, Jaroslaw P.

Published
2012
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87. Seroreactivity to LGL leukemia-specific epitopes in aplastic anemia, myelodysplastic syndrome and paroxysmal nocturnal hemoglobinuria: Results of a bone marrow failure consortium study

Author

Nyland, Susan Bell, Krissinger, Daniel J., Clemente, Michael J., Irby, Rosalyn B., Baab, Kendall Thomas, Jarbadan, Nancy Ruth, Sokol, Lubomir, Schaefer, Eric, Liao, Jason, Cuthbertson, David, Epling-Burnette, Pearlie, Paquette, Ronald, List, Alan F., Maciejewski, Jaroslaw P., and Loughran, Thomas P., Jr.

Published
2012
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89. S176: FUNCTIONAL AND ANTIGEN‐SPECIFIC CHARACTERIZATION OF IMMUNE CELLS AT THE SINGLE‐CELL LEVEL REVEALS CONVERGENCE OF ADAPTIVE AND INNATE IMMUNITY IN IMMUNE APLASTIC ANEMIA.

Author

Huuhtanen, Jani, Lundgren, Sofie, Keränen, Mikko, Feng, Xingim, Dulau‐Florea, Alina, Patel, Bhavisha, Zaimoku, Yoshitaka, Kerr, Cassandra, Jokinen, Emmi, Heinonen, Markus, Rajala, Hanna, Siitonen, Sanna, Ebeling, Freja, Ryland, Georgina, Fox, Lucy, Blombery, Piers, Hellström‐Lindberg, Eva, Maciejewski, Jaroslaw P., Young, Neal S., and Lähdesmäki, Harri

Published
2023
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94. Optimization of Therapy for Severe Aplastic Anemia Based on Clinical, Biologic, and Treatment Response Parameters: Conclusions of an International Working Group on Severe Aplastic Anemia Convened by the Blood and Marrow Transplant Clinical Trials Network, March 2010

Author

Pulsipher, Michael A., Young, Neal S., Tolar, Jakub, Risitano, Antonio M., Deeg, H. Joachim, Anderlini, Paolo, Calado, Rodrigo, Kojima, Seiji, Eapen, Mary, Harris, Richard, Scheinberg, Phillip, Savage, Sharon, Maciejewski, Jaroslaw P., Tiu, Ramon V., DiFronzo, Nancy, Horowitz, Mary M., and Antin, Joseph H.

Published
2011
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95. Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria

Author

Shen, Wenyi, Clemente, Michael J., Hosono, Naoko, Yoshida, Kenichi, Przychodzen, Bartlomiej, Yoshizato, Tetsuichi, Shiraishi, Yuichi, Miyano, Satoru, Ogawa, Seishi, Maciejewski, Jaroslaw P., and Makishima, Hideki

Subjects
Gene mutations -- Identification and classification, Hemoglobinuria, Paroxysmal -- Genetic aspects -- Development and progression, Health care industry
Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disease of hematopoietic stem cells that is associated with hemolysis, marrow failure, and thrombophilia. PNH has been considered a monogenic disease that results from somatic mutations in the gene encoding PIGA, which is required for biosynthesis of glycosylphosphatidylinisotol-anchored (GPI-anchored) proteins. The loss of certain GPI-anchored proteins is hypothesized to provide the mutant clone with an extrinsic growth advantage, but some features of PNH argue that there are intrinsic drivers of clonal expansion. Here, we performed whole-exome sequencing of paired [PNH.sup.+] and [PNH.sup.-] fractions on samples taken from 12 patients as well as targeted deep sequencing of an additional 36 PNH patients. We identified additional somatic mutations that resulted in a complex hierarchical clonal architecture, similar to that observed in myeloid neoplasms. In addition to mutations in PIGA, mutations were found in genes known to be involved in myeloid neoplasm pathogenesis, including TET2, SUZ12, U2AF1, and JAK2. Clonal analysis indicated that these additional mutations arose either as a subclone within the PIGA-mutant population, or prior to PIGA mutation. Together, our data indicate that in addition to PIGA mutations, accessory genetic events are frequent in PNH, suggesting a stepwise clonal evolution derived from a singular stem cell clone., Introduction Paroxysmal nocturnal hemoglobinuria (PNH), a prototypical disease of hematopoietic stem cells, is characterized by the clinical triad of intravascular hemolysis, thrombophilia, and bone marrow failure (1). While clonal, PNH [...]

Published
2014
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97. Impact of SNP array karyotyping on the diagnosis and the outcome of chronic myelomonocytic leukemia with low risk cytogenetic features or no metaphases

Author

Palomo, Laura, Xicoy, Blanca, Garcia, Olga, Mallo, Mar, Ademà, Vera, Cabezón, Marta, Arnan, Montse, Pomares, Helena, Larrayoz, María José, Calasanz, María José, Maciejewski, Jaroslaw P., Huang, Dayong, Shih, Lee-Yung, Ogawa, Seishi, Cervera, Jose, Such, Esperanza, Coll, Rosa, Grau, Javier, Solé, Francesc, and Zamora, Lurdes

Published
2016
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98. Concomitant Immunosuppressive Therapy and Eculizumab Use in Patients with Paroxysmal Nocturnal Hemoglobinuria: An International PNH Registry Analysis.

Author

Hill, Anita, de Latour, Régis Peffault, Kulasekararaj, Austin G., Griffin, Morag, Brodsky, Robert A., Maciejewski, Jaroslaw P., Marantz, Jing L., Gustovic, Philippe, and Schrezenmeier, Hubert

Subjects
PAROXYSMAL hemoglobinuria, IMMUNOSUPPRESSIVE agents, RED blood cell transfusion, COMPLEMENT (Immunology), ECULIZUMAB, APLASTIC anemia
Abstract

Introduction: Complement C5 inhibitor eculizumab is the first approved treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder caused by uncontrolled terminal complement activation. Approximately 50% of patients with aplastic anemia (AA) have PNH cells. Limited data are available for patients with AA-PNH taking concomitant immunosuppressive therapy (IST) and eculizumab. Methods: Data from the International PNH Registry (NCT01374360) were used to evaluate the safety and effectiveness of eculizumab and IST in patients taking IST followed by concomitant eculizumab (IST + c-Ecu) or eculizumab followed by concomitant IST (Ecu + c-IST). Results: As of January 1, 2018, 181 Registry-enrolled patients were included in the eculizumab effectiveness analyses (n = 138, IST + c-Ecu; n = 43, Ecu + c-IST); 87 additional patients received IST alone. Reductions from baseline with eculizumab were observed in the least squares mean lactate dehydrogenase ratio (IST + c-Ecu, −3.4; Ecu + c-IST, −3.5); thrombotic event incidence rates were similar between groups (IST + c-Ecu, 1.3; Ecu + c-IST, 0.7). Red blood cell transfusion rate ratios decreased from baseline for IST + c-Ecu (0.7) and increased for Ecu + c-IST (1.2); there were none for IST alone. Hematological parameters generally improved for IST + c-Ecu and IST alone, and changed minimally or worsened for Ecu + c-IST. Safety signals were generally consistent with those previously described for the respective therapies. Discussion/conclusion: Although some intergroup differences were seen, concomitant eculizumab and IST were safe and effective regardless of treatment sequence. [ABSTRACT FROM AUTHOR]

Published
2023
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100. Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value.

Author

Pagliuca, Simona, Gurnari, Carmelo, Zhang, Keman, Kewan, Tariq, Bahaj, Waled, Mori, Minako, Nautiyal, Ishani, Rubio, Marie Thérèse, Ferraro, Francesca, Maciejewski, Jaroslaw P., Wang, Li, and Visconte, Valeria

Subjects
ACUTE myeloid leukemia, PROGNOSIS, BONE marrow, HEMATOPOIETIC stem cells, HEMATOPOIESIS, TRANSCRIPTOMES, GENE expression
Abstract

The V-domain Ig suppressor of T-cell activation (VISTA) has been recognized as a critical negative regulator of antitumor immune response and is gaining growing interest as a potential pharmacological target in immunotherapy. This molecule is highly expressed in hematopoietic stem cells and myeloid compartment, and it has been found upmodulated in acute myeloid leukemia (AML). However, VISTA-associated immune features are relatively unexplored in myeloid malignancies. Herein, we aimed to explore whether this immune checkpoint regulator could play a role in the generation of an immune escape environment in AML patients. We characterized VISTA mRNA expression levels in leukemia cell lines and in large publicly available cohorts of specimens from bone marrow of healthy individuals and AML patients at diagnosis by deploying bulk and single-cell RNA sequencing. We also defined the correlations with leukemia-associated burden using results of whole-exome sequencing of AML samples at disease onset. We showed that VISTA expression linearly increased across the myeloid differentiation tree in normal hematopoiesis. Accordingly, its transcript was highly enriched in AML cell lines as well as in AML patients at diagnosis presenting with myelomonocytic and monocytic differentiation. A strong correlation was seen with NPM1 mutations regardless of the presence of FLT3 lesions. Furthermore, VISTA expression levels at baseline correlated with disease recurrence in patients with normal karyotype and NPM1 mutations, a subgroup traditionally considered as favorable according to current diagnostic schemes. Indeed, when compared to patients with long-term remission (>5 years after standard chemotherapy regimens), cases relapsing within 2 years from diagnosis had increased VISTA expression in both leukemia and T cells. Our results suggest a rationale for developing VISTA-targeted therapeutic strategies to treat molecularly defined subgroups of AML patients to prevent disease recurrence and treatment resistance. [ABSTRACT FROM AUTHOR]

Published
2022
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