Myeloid Disease Mutations of Splicing Factor SRSF2 Cause G2-M Arrest and Skewed Differentiation of Human Hematopoietic Stem and Progenitor Cells.
Name:
Myeloid Disease Mutations_2018.pdf
Size:
9.496Mb
Format:
PDF
Description:
Final Accepted Manuscript
Author
Bapat, AditiKeita, Nakia
Martelly, William
Kang, Paul
Seet, Christopher
Jacobsen, Jeffery R
Stoilov, Peter
Hu, Chengcheng
Crooks, Gay M
Sharma, Shalini
Affiliation
Univ Arizona, Coll Med Phoenix, Dept Basic Med SciUniv Arizona, Mel & Enid Zuckerman Coll Publ Hlth Phoenix, Dept Epidemiol & Biostat
Issue Date
2018-07-13Keywords
Acute myelogenous leukemiaApoptosis
CD34+
Differentiation
Hematologic malignancies
Hematopoietic stem cells
Proliferation
Umbilical cord blood
Metadata
Show full item recordPublisher
WILEYCitation
Bapat, A. , Keita, N. , Martelly, W. , Kang, P. , Seet, C. , Jacobsen, J. R., Stoilov, P. , Hu, C. , Crooks, G. M. and Sharma, S. (2018), Myeloid Disease Mutations of Splicing Factor SRSF2 Cause G2‐M Arrest and Skewed Differentiation of Human Hematopoietic Stem and Progenitor Cells. Stem Cells, 36: 1663-1675. doi:10.1002/stem.2885Journal
STEM CELLSRights
© 2018 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.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;36:1663-1675Note
6 month embargo; first published: 13 July 2018ISSN
1549-4918PubMed ID
30004607Version
Final accepted manuscriptSponsors
Broad Stem Cell Research Center at University of California, Los Angeles (UCLA); Arizona Cord Blood Program; UCLA Center for AIDS Research Virology Core Lab [5P30 AI028697]; National Institutes of Health/National Cancer Institute [R21CA170786]; American Cancer Society [74-001-34-IRG]; Arizona Area Health Education Centers (AzAHEC) program; Department of Defense Breast Cancer Research program [BC142286]; National Institutes of Health/National Center for Advancing Translational Science [KL2TR001882]; UCLA Broad Stem Cell Research Center clinical fellowship; Flow Cytometry Core Facilities at the University of Arizona College of MedicinePhoenixae974a485f413a2113503eed53cd6c53
10.1002/stem.2885
Scopus Count
Collections
Related articles
- Alteration of the SETBP1 gene and splicing pathway genes SF3B1, U2AF1, and SRSF2 in childhood acute myeloid leukemia.
- Authors: Choi HW, Kim HR, Baek HJ, Kook H, Cho D, Shin JH, Suh SP, Ryang DW, Shin MG
- Issue date: 2015 Jan
- Impact of allogeneic hematopoietic cell transplant in patients with myeloid neoplasms carrying spliceosomal mutations.
- Authors: Hamilton BK, Visconte V, Jia X, Tabarroki A, Makishima H, Hasrouni E, Abounader D, Kalaycio M, Sekeres MA, Sobecks R, Duong Liu H, Bolwell B, Maciejewski JP, Copelan E, Tiu RV
- Issue date: 2016 Jun
- Mutational analysis of splicing machinery genes SF3B1, U2AF1 and SRSF2 in myelodysplasia and other common tumors.
- Authors: Je EM, Yoo NJ, Kim YJ, Kim MS, Lee SH
- Issue date: 2013 Jul
- Clinical presentation and differential splicing of SRSF2, U2AF1 and SF3B1 mutations in patients with acute myeloid leukemia.
- Authors: Bamopoulos SA, Batcha AMN, Jurinovic V, Rothenberg-Thurley M, Janke H, Ksienzyk B, Philippou-Massier J, Graf A, Krebs S, Blum H, Schneider S, Konstandin N, Sauerland MC, Görlich D, Berdel WE, Woermann BJ, Bohlander SK, Canzar S, Mansmann U, Hiddemann W, Braess J, Spiekermann K, Metzeler KH, Herold T
- Issue date: 2020 Oct
- Mutation clonal burden and allogeneic hematopoietic cell transplantation outcomes in acute myeloid leukemia and myelodysplastic syndromes.
- Authors: Hamilton BK, Rybicki L, Hirsch C, Przychodzen B, Nazha A, Gerds AT, Hanna R, Kalaycio M, Sekeres MA, Sobecks R, de Lima M, Majhail NS, Maciejewski J
- Issue date: 2019 Aug