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Neonatal expression of RNA-binding protein IGF2BP3 regulates the human fetal-adult megakaryocyte transition.
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; Sansó, Miriam; Fisher, Robert P; Iancu-Rubin, Camelia; Goldfarb, Adam N.
Afiliación
  • Elagib KE; Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Lu CH; Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Mosoyan G; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • Khalil S; Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Zasadzinska E; Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, Charlottesville, Virginia, USA.
  • Foltz DR; Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, Charlottesville, Virginia, USA.
  • Balogh P; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • Gru AA; Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Fuchs DA; Department of Pathology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
  • Rimsza LM; Department of Pathology, University of Arizona College of Medicine, Tucson, Arizona, USA.
  • Verhoeyen E; Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
  • Sansó M; Centre International de Recherche en Infectiologie (CIRI), Team EVIR, Inserm, U1111, Ecole Normale Supériere de Lyon, Université Lyon 1, CNRS, UMR5308, Lyon, France.
  • Fisher RP; Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Nice, France.
  • Iancu-Rubin C; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • Goldfarb AN; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
J Clin Invest ; 127(6): 2365-2377, 2017 Jun 01.
Article en En | MEDLINE | ID: mdl-28481226
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Megacariocitos / Proteínas de Unión al ARN Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Newborn Idioma: En Revista: J Clin Invest Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Megacariocitos / Proteínas de Unión al ARN Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Newborn Idioma: En Revista: J Clin Invest Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos