EVI1 overexpression reprograms hematopoiesis via upregulation of Spi1 transcription

Edward Ayoub, Michael P. Wilson, Kathleen E. McGrath, Allison J. Li, Benjamin J. Frisch, James Palis, Laura M. Calvi, Yi Zhang () and Archibald S. Perkins ()
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Edward Ayoub: University of Rochester Medical Center
Michael P. Wilson: University of Rochester Medical Center
Kathleen E. McGrath: University of Rochester Medical Center
Allison J. Li: University of Rochester Medical Center
Benjamin J. Frisch: University of Rochester Medical Center
James Palis: University of Rochester Medical Center
Laura M. Calvi: University of Rochester Medical Center
Yi Zhang: University of Rochester Medical Center
Archibald S. Perkins: University of Rochester Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06208-y

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