Altered Runx1 subnuclear targeting enhances myeloid cell proliferation and blocks differentiation by activating a miR-24/MKP-7/MAPK network

Sayyed K. Zaidi, Christopher R. Dowdy, Andre J. Van Wijnen, Jane B. Lian, Azra Raza, Janet L. Stein, Carlo M. Croce, Gary S. Stein

Research output: Contribution to journalArticle

92 Scopus citations

Abstract

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.Ex pression 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.

Original languageEnglish (US)
Pages (from-to)8249-8255
Number of pages7
JournalCancer research
Volume69
Issue number21
DOIs
StatePublished - Nov 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zaidi, S. K., Dowdy, C. R., Van Wijnen, A. J., Lian, J. B., Raza, A., Stein, J. L., Croce, C. M., & Stein, G. S. (2009). Altered Runx1 subnuclear targeting enhances myeloid cell proliferation and blocks differentiation by activating a miR-24/MKP-7/MAPK network. Cancer research, 69(21), 8249-8255. https://doi.org/10.1158/0008-5472.CAN-09-1567