Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression.
Hoxa9 and Meis1 also cooperate to induce aggressive AML with high Flt3 expression in mice, suggesting an important role for Flt3 in Hoxa9/Meis1-induced leukemogenesis.
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></i>.
Moreover, we identified PBX2, a well-known homeodomain protein whose aberrant expression enhances HoxA9-dependent leukemogenesis, as a novel let-7c target that may contribute to the AML phenotype.
Functional relevance of GPR56 expression was validated in mice, in which co-expression of Gpr56 significantly accelerated HOXA9-induced leukemogenesis and vice versa knockdown of Gpr56 delayed onset of HOXA9/MEIS1-induced AML.