EVI1 overexpression reprograms hematopoiesis via upregulation of Spi1 transcription

• DOI: 10.1038/s41467-018-06208-y
• Publication Date: 2018-10-08T10:43:31Z
• Authors: Edward Ayoub; Michael P. Wilson; Kathleen E. McGrath; Allison J. Li; Benjamin J. Frisch; James Palis; Laura M. Calvi; Yi Zhang; Archibald S. Perkins
• Keywords: Myelopoiesis; Lymphopoiesis

Inv(3q26) and t(3:3)(q21;q26) are specific to poor-prognosis myeloid malignancies, result in marked overexpression of EVI1, a zinc-finger transcription factor myeloid-specific oncoprotein. Despite extensive study, the mechanism by which EVI1 contributes malignancy remains unclear. Here we describe new mouse model that mimics transcriptional effects 3q26 rearrangement. We show causes global distortion hematopoiesis, with suppression erythropoiesis lymphopoiesis, premalignant expansion myelopoiesis eventually results leukemic transformation. skewing is dependent on DNA binding upregulates Spi1, encoding master regulator PU.1. binds -14 kb upstream regulatory element (-14kbURE) at Spi1; knockdown Spi1 dampens skewing. Furthermore, deletion -14kbURE abrogates hematopoietic stem cells. These findings support novel leukemogenesis through overexpression.