Show simple item record

dc.contributor.authorBapat, Aditi
dc.contributor.authorKeita, Nakia
dc.contributor.authorMartelly, William
dc.contributor.authorKang, Paul
dc.contributor.authorSeet, Christopher
dc.contributor.authorJacobsen, Jeffery R
dc.contributor.authorStoilov, Peter
dc.contributor.authorHu, Chengcheng
dc.contributor.authorCrooks, Gay M
dc.contributor.authorSharma, Shalini
dc.date.accessioned2019-03-05T21:07:46Z
dc.date.available2019-03-05T21:07:46Z
dc.date.issued2018-07-13
dc.identifier.citationBapat, 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.2885en_US
dc.identifier.issn1549-4918
dc.identifier.pmid30004607
dc.identifier.doi10.1002/stem.2885
dc.identifier.urihttp://hdl.handle.net/10150/631785
dc.description.abstractMyeloid 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;36:1663-1675en_US
dc.description.sponsorshipBroad 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 MedicinePhoenixen_US
dc.language.isoenen_US
dc.publisherWILEYen_US
dc.rights© 2018 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.en_US
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectAcute myelogenous leukemiaen_US
dc.subjectApoptosisen_US
dc.subjectCD34+en_US
dc.subjectDifferentiationen_US
dc.subjectHematologic malignanciesen_US
dc.subjectHematopoietic stem cellsen_US
dc.subjectProliferationen_US
dc.subjectUmbilical cord blooden_US
dc.titleMyeloid Disease Mutations of Splicing Factor SRSF2 Cause G2-M Arrest and Skewed Differentiation of Human Hematopoietic Stem and Progenitor Cells.en_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Coll Med Phoenix, Dept Basic Med Scien_US
dc.contributor.departmentUniv Arizona, Mel & Enid Zuckerman Coll Publ Hlth Phoenix, Dept Epidemiol & Biostaten_US
dc.identifier.journalSTEM CELLSen_US
dc.description.note6 month embargo; first published: 13 July 2018en_US
dc.description.collectioninformationThis 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.en_US
dc.eprint.versionFinal accepted manuscripten_US
dc.source.journaltitleStem cells (Dayton, Ohio)
refterms.dateFOA2019-01-13T00:00:00Z


Files in this item

Thumbnail
Name:
Myeloid Disease Mutations_2018.pdf
Size:
9.496Mb
Format:
PDF
Description:
Final Accepted Manuscript

This item appears in the following Collection(s)

Show simple item record