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dc.contributor.authorElagib, Kamaleldin E.
dc.contributor.authorLu, Chih-Huan
dc.contributor.authorMosoyan, Goar
dc.contributor.authorKhalil, Shadi
dc.contributor.authorZasadzinska, Ewelina
dc.contributor.authorFoltz, Daniel R.
dc.contributor.authorBalogh, Peter
dc.contributor.authorGru, Alejandro A.
dc.contributor.authorFuchs, Deborah A.
dc.contributor.authorRimsza, Lisa M.
dc.contributor.authorVerhoeyen, Els
dc.contributor.authorSanso, Miriam
dc.contributor.authorFisher, Robert P.
dc.contributor.authorIancu-Rubin, Camelia
dc.contributor.authorGoldfarb, Adam N.
dc.date.accessioned2017-06-27T18:14:38Z
dc.date.available2017-06-27T18:14:38Z
dc.date.issued2017-05-08
dc.identifier.citationNeonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition 2017, 127 (6):2365 Journal of Clinical Investigationen
dc.identifier.issn0021-9738
dc.identifier.issn1558-8238
dc.identifier.pmid28481226
dc.identifier.doi10.1172/JCI88936
dc.identifier.urihttp://hdl.handle.net/10150/624443
dc.description.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.
dc.description.sponsorshipNIH [DK090926, HL130550, T32 CA009109-39]en
dc.language.isoenen
dc.publisherAMER SOC CLINICAL INVESTIGATION INCen
dc.relation.urlhttps://www.jci.org/articles/view/88936en
dc.rightsCopyright © 2017, American Society for Clinical Investigationen
dc.titleNeonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transitionen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Coll Med, Dept Patholen
dc.identifier.journalJournal of Clinical Investigationen
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
dc.eprint.versionFinal published versionen
refterms.dateFOA2018-05-29T16:17:57Z
html.description.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.


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