Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition
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.
Affiliation
Univ Arizona, Coll Med, Dept PatholIssue Date
2017-05-08
Metadata
Show full item recordPublisher
AMER SOC CLINICAL INVESTIGATION INCCitation
Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition 2017, 127 (6):2365 Journal of Clinical InvestigationRights
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
0021-97381558-8238
PubMed ID
28481226DOI
10.1172/JCI88936Version
Final published versionSponsors
NIH [DK090926, HL130550, T32 CA009109-39]Additional Links
https://www.jci.org/articles/view/88936ae974a485f413a2113503eed53cd6c53
10.1172/JCI88936