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Myeloid Disease Mutations of Splicing Factor SRSF2 Cause G2-M Arrest and Skewed Differentiation of Human Hematopoietic Stem and Progenitor Cells.
Bapat, Aditi; Keita, Nakia; Martelly, William; Kang, Paul; Seet, Christopher; Jacobsen, Jeffery R; Stoilov, Peter; Hu, Chengcheng; Crooks, Gay M; Sharma, Shalini.
Afiliação
  • Bapat A; Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, Arizona, USA.
  • Keita N; Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, Arizona, USA.
  • Martelly W; Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, Arizona, USA.
  • Kang P; Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health-Phoenix, University of Arizona, Phoenix, Arizona, USA.
  • Seet C; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
  • Jacobsen JR; Department of Pathology and Laboratory Medicine, Phoenix Children's Hospital, Phoenix, Arizona, USA.
  • Stoilov P; Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, West Virginia, USA.
  • Hu C; Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health-Phoenix, University of Arizona, Phoenix, Arizona, USA.
  • Crooks GM; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
  • Sharma S; Department of Basic Medical Sciences, College of Medicine-Phoenix, University of Arizona, Phoenix, Arizona, USA.
Stem Cells ; 36(11): 1663-1675, 2018 11.
Article em En | MEDLINE | ID: mdl-30004607
ABSTRACT
Myeloid malignancies, including myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia, are characterized by abnormal proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs). Reports on analysis of bone marrow samples from patients have revealed a high incidence of mutations in splicing factors in early stem and progenitor cell clones, but the mechanisms underlying transformation of HSPCs harboring these mutations remain unknown. Using ex vivo cultures of primary human CD34+ cells as a model, we find that mutations in splicing factors SRSF2 and U2AF1 exert distinct effects on proliferation and differentiation of HSPCs. SRSF2 mutations cause a dramatic inhibition of proliferation via a G2-M phase arrest and induction of apoptosis. U2AF1 mutations, conversely, do not significantly affect proliferation. Mutations in both SRSF2 and U2AF1 cause abnormal differentiation by skewing granulo-monocytic differentiation toward monocytes but elicit diverse effects on megakaryo-erythroid differentiation. The SRSF2 mutations skew differentiation toward megakaryocytes whereas U2AF1 mutations cause an increase in the erythroid cell populations. These distinct functional consequences indicate that SRSF2 and U2AF1 mutations have cell context-specific effects and that the generation of myeloid disease phenotype by mutations in the genes coding these two proteins likely involves different intracellular mechanisms. Stem Cells 2018;361663-1675.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco / Leucemia Mieloide Aguda / Transplante de Células-Tronco Hematopoéticas / Condicionamento Pré-Transplante / Pontos de Checagem da Fase G2 do Ciclo Celular / Fatores de Processamento de RNA Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco / Leucemia Mieloide Aguda / Transplante de Células-Tronco Hematopoéticas / Condicionamento Pré-Transplante / Pontos de Checagem da Fase G2 do Ciclo Celular / Fatores de Processamento de RNA Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article