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    Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition

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    Author
    Elagib, Kamaleldin E.
    Lu, Chih-Huan
    Mosoyan, Goar
    Khalil, Shadi
    Zasadzinska, Ewelina
    Foltz, Daniel R.
    Balogh, Peter
    Gru, Alejandro A.
    Fuchs, Deborah A.
    Rimsza, Lisa M.
    Verhoeyen, Els
    Sanso, Miriam
    Fisher, Robert P.
    Iancu-Rubin, Camelia
    Goldfarb, Adam N.
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    Affiliation
    Univ Arizona, Coll Med, Dept Pathol
    Issue Date
    2017-05-08
    
    Metadata
    Show full item record
    Publisher
    AMER SOC CLINICAL INVESTIGATION INC
    Citation
    Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition 2017, 127 (6):2365 Journal of Clinical Investigation
    Journal
    Journal of Clinical Investigation
    Rights
    Copyright © 2017, American Society for Clinical Investigation.
    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
    Hematopoietic transitions that accompany fetal development, such as erythroid globin chain switching, play important roles in normal physiology and disease development. In the megakaryocyte lineage, human fetal progenitors do not execute the adult morphogenesis program of enlargement, polyploidization, and proplatelet formation. Although these defects decline with gestational stage, they remain sufficiently severe at birth to predispose newborns to thrombocytopenia. These defects may also contribute to inferior platelet recovery after cord blood stem cell transplantation and may underlie inefficient platelet production by megakaryocytes derived from pluripotent stem cells. In this study, comparison of neonatal versus adult human progenitors has identified a blockade in the specialized positive transcription elongation factor b (P-TEFb) activation mechanism that is known to drive adult megakaryocyte morphogenesis. This blockade resulted from neonatal-specific expression of an oncofetal RNA-binding protein, IGF2BP3, which prevented the destabilization of the nuclear RNA 7SK, a process normally associated with adult megakaryocytic P-TEFb activation. Knockdown of IGF2BP3 sufficed to confer both phenotypic and molecular features of adult-type cells on neonatal megakaryocytes. Pharmacologic inhibition of IGF2BP3 expression via bromodomain and extraterminal domain (BET) inhibition also elicited adult features in neonatal megakaryocytes. These results identify IGF2BP3 as a human ontogenic master switch that restricts megakaryocyte development by modulating a lineage-specific P-TEFb activation mechanism, revealing potential strategies toward enhancing platelet production.
    ISSN
    0021-9738
    1558-8238
    PubMed ID
    28481226
    DOI
    10.1172/JCI88936
    Version
    Final published version
    Sponsors
    NIH [DK090926, HL130550, T32 CA009109-39]
    Additional Links
    https://www.jci.org/articles/view/88936
    ae974a485f413a2113503eed53cd6c53
    10.1172/JCI88936
    Scopus Count
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    UA Faculty Publications

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