Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition
AuthorElagib, Kamaleldin E.
Foltz, Daniel R.
Gru, Alejandro A.
Fuchs, Deborah A.
Rimsza, Lisa M.
Fisher, Robert P.
Goldfarb, Adam N.
AffiliationUniv Arizona, Coll Med, Dept Pathol
MetadataShow full item record
PublisherAMER SOC CLINICAL INVESTIGATION INC
CitationNeonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition 2017, 127 (6):2365 Journal of Clinical Investigation
RightsCopyright © 2017, American Society for Clinical Investigation
Collection InformationThis 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 firstname.lastname@example.org.
AbstractHematopoietic 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.
VersionFinal published version
SponsorsNIH [DK090926, HL130550, T32 CA009109-39]
- Calpain 2 activation of P-TEFb drives megakaryocyte morphogenesis and is disrupted by leukemogenic GATA1 mutation.
- Authors: Elagib KE, Rubinstein JD, Delehanty LL, Ngoh VS, Greer PA, Li S, Lee JK, Li Z, Orkin SH, Mihaylov IS, Goldfarb AN
- Issue date: 2013 Dec 23
- PDCD2 knockdown inhibits erythroid but not megakaryocytic lineage differentiation of human hematopoietic stem/progenitor cells.
- Authors: Kokorina NA, Granier CJ, Zakharkin SO, Davis S, Rabson AB, Sabaawy HE
- Issue date: 2012 Dec
- Mice lacking transcription factor NF-E2 provide in vivo validation of the proplatelet model of thrombocytopoiesis and show a platelet production defect that is intrinsic to megakaryocytes.
- Authors: Lecine P, Villeval JL, Vyas P, Swencki B, Xu Y, Shivdasani RA
- Issue date: 1998 Sep 1
- Circulating megakaryocytes and their progenitors in early thrombocytopenia in preterm neonates.
- Authors: Murray NA, Roberts IA
- Issue date: 1996 Jul
- miR-125b modulates megakaryocyte maturation by targeting the cell-cycle inhibitor p19<sup>INK4D</sup>.
- Authors: Qu M, Fang F, Zou X, Zeng Q, Fan Z, Chen L, Yue W, Xie X, Pei X
- Issue date: 2016 Oct 20