<i>MIR142</i> Loss-of-Function Mutations Derepress ASH1L to Increase <i>HOXA</i> Gene Expression and Promote Leukemogenesis

Abstract

Point mutations in the seed sequence of miR-142-3p are present in a subset of acute myelogenous leukemia (AML) and in several subtypes of B-cell lymphoma. Here, we show that mutations associated with AML result both in loss of miR-142-3p function and in decreased miR-142-5p expression. <i>Mir142</i> loss altered the hematopoietic differentiation of multipotent hematopoietic progenitors, enhancing their myeloid potential while suppressing their lymphoid potential. During hematopoietic maturation, loss of <i>Mir142</i> increased ASH1L protein expression and consequently resulted in the aberrant maintenance of <i>Hoxa</i> gene expression in myeloid-committed hematopoietic progenitors. <i>Mir142</i> loss also enhanced the disease-initiating activity of <i>IDH2</i>-mutant hematopoietic cells in mice. Together these data suggest a novel model in which miR-142, through repression of ASH1L activity, plays a key role in suppressing <i>HOXA9/A10</i> expression during normal myeloid differentiation. AML-associated loss-of-function mutations of <i>MIR142</i> disrupt this negative signaling pathway, resulting in sustained <i>HOXA9/A10</i> expression in myeloid progenitors/myeloblasts and ultimately contributing to leukemic transformation.<b>Significance:</b> These findings provide mechanistic insights into the role of miRNAs in leukemogenesis and hematopoietic stem cell function. <i>Cancer Res; 78(13); 3510-21. ©2018 AACR</i>.