Altered Runx1 Subnuclear Targeting Enhances Myeloid Cell Proliferation and Blocks Differentiation by activating a miR-24/MKP-7/MAP Kinase Network

Disruption of Runx1/AML1 subnuclear localization, either by a single amino acid substitution or by a chromosomal translocation (e.g. t(8;21)), is linked to the etiology of acute myeloid leukemia (AML). Here we show that this defect induces a select set of micro-RNAs (miRs) in myeloid progenitor cells and AML patients with t(8;21). Both Runx1 and the t(8;21)-encoded AML1-ETO occupy the miR-24-23-27 locus and reciprocally control miR-24 transcription. miR-24 directly downregulates MAPK Phosphatase-7 and enhances phosphorylation of both JNK and p38 kinases. Expression of miR-24 stimulates myeloid cell growth, renders proliferation independent of IL3 and blocks granulocytic differentiation. Thus, compromised Runx1 function induces a miR-dependent mechanism that, through MAPK signaling, enhances myeloid proliferation but blocks differentiation, key steps that contribute to leukemia.