Myeloid Disease Mutations of Splicing Factor SRSF2 Cause G2-M Arrest and Skewed Differentiation of Human Hematopoietic Stem and Progenitor Cells
| Autor: | Aditi Bapat, Nakia Keita, William Martelly, Paul Kang, Christopher Seet, Jeffery R. Jacobsen, Peter Stoilov, Chengcheng Hu, Gay M. Crooks, Shalini Sharma |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Myeloid Technology Transplantation Conditioning Proliferation CD34 Acute myelogenous leukemia Apoptosis Regenerative Medicine Medical and Health Sciences Umbilical cord blood 0302 clinical medicine Stem Cell Research - Nonembryonic - Human Cancer Stem Cells 2.1 Biological and endogenous factors Aetiology Cancer CD34(+) Tumor Leukemia Stem Cells Hematopoietic Stem Cell Transplantation Myeloid leukemia Hematology Biological Sciences 3. Good health G2 Phase Cell Cycle Checkpoints Haematopoiesis Leukemia Myeloid Acute medicine.anatomical_structure 030220 oncology & carcinogenesis Differentiation Molecular Medicine Stem Cell Research - Nonembryonic - Non-Human RNA Splicing Factors Stem cell CD34+ Immunology Biology Acute Cell Line 03 medical and health sciences Rare Diseases Cell Line Tumor medicine Genetics Humans Progenitor cell Myelodysplastic syndromes Cell Biology medicine.disease Stem Cell Research 030104 developmental biology Mutation Cancer research Hematologic malignancies Bone marrow Hematopoietic stem cells Developmental Biology |
| Zdroj: | Stem cells (Dayton, Ohio), vol 36, iss 11 Stem Cells (Dayton, Ohio) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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