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EVI1 overexpression reprograms hematopoiesis via upregulation of Spi1 transcription.
Ayoub, Edward; Wilson, Michael P; McGrath, Kathleen E; Li, Allison J; Frisch, Benjamin J; Palis, James; Calvi, Laura M; Zhang, Yi; Perkins, Archibald S.
Afiliación
  • Ayoub E; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • Wilson MP; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • McGrath KE; Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • Li AJ; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • Frisch BJ; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • Palis J; Department of Pediatrics and Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • Calvi LM; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • Zhang Y; Department of Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • Perkins AS; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Nat Commun ; 9(1): 4239, 2018 10 12.
Article en En | MEDLINE | ID: mdl-30315161
Inv(3q26) and t(3:3)(q21;q26) are specific to poor-prognosis myeloid malignancies, and result in marked overexpression of EVI1, a zinc-finger transcription factor and myeloid-specific oncoprotein. Despite extensive study, the mechanism by which EVI1 contributes to myeloid malignancy remains unclear. Here we describe a new mouse model that mimics the transcriptional effects of 3q26 rearrangement. We show that EVI1 overexpression causes global distortion of hematopoiesis, with suppression of erythropoiesis and lymphopoiesis, and marked premalignant expansion of myelopoiesis that eventually results in leukemic transformation. We show that myeloid skewing is dependent on DNA binding by EVI1, which upregulates Spi1, encoding master myeloid regulator PU.1. We show that EVI1 binds to the -14 kb upstream regulatory element (-14kbURE) at Spi1; knockdown of Spi1 dampens the myeloid skewing. Furthermore, deletion of the -14kbURE at Spi1 abrogates the effects of EVI1 on hematopoietic stem cells. These findings support a novel mechanism of leukemogenesis through EVI1 overexpression.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transactivadores / Proteínas Proto-Oncogénicas / Proteína del Locus del Complejo MDS1 y EV11 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transactivadores / Proteínas Proto-Oncogénicas / Proteína del Locus del Complejo MDS1 y EV11 Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido