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

¹ Department of Cell Biology, University of Massachusetts Medical School and Cancer Center, Worcester, Massachusetts; ² Department of Molecular Virology, Immunology & Medical Genetics-Human Cancer Genetics, College of Medicine, Ohio State University, Columbus, Ohio; and ³ St. Vincent's Comprehensive Cancer Center, New York, New York

Requests for reprints: Gary S. Stein, University of Massachusetts Medical School, 55 Lake Avenue, North, Worcester, MA 01655. Phone: 508-856-5625; Fax: 508-856-6800; E-mail: Gary.Stein{at}umassmed.edu.

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 (miR) 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 mitogen-activated protein kinase (MAPK) phosphatase-7 and enhances phosphorylation of both c-jun-NH₂-kinase and p38 kinases. Expression of miR-24 stimulates myeloid cell growth, renders proliferation independent of interleukin-3, 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. [Cancer Res 2009;69(21):8249–55]

Key Words: cancer • leukemia • AML1-ETO • chromosomal translocation • micro-RNA • AML