Altered Runx1 subnuclear targeting enhances myeloid cell proliferation and blocks differentiation by activating a miR-24/MKP-7/MAPK network
Department of Cell Biology
Cell Proliferation; Cell Differentiation; Leukemia, Myeloid, Acute; Core Binding Factor Alpha 2 Subunit; Humans; MicroRNAs; Transcription Factors; Mitogen-Activated Protein Kinase Phosphatases
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-NH(2)-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.
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Citation: Cancer Res. 2009 Nov 1;69(21):8249-55. Epub 2009 Oct 13. Link to article on publisher's site
Zaidi, Sayyed K.; Dowdy, Christopher R.; Van Wijnen, Andre J.; Lian, Jane B.; Raza, Azra; Stein, Janet L.; Croce, Carlo M.; and Stein, Gary S., "Altered Runx1 subnuclear targeting enhances myeloid cell proliferation and blocks differentiation by activating a miR-24/MKP-7/MAPK network" (2009). Cell and Developmental Biology Publications and Presentations. Paper 87.