The oncogenic MicroRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation

Su Jung Song, Keisuke Ito, Ugo Ala, Lev Kats, Kaitlyn Webster, Su Ming Sun, Mojca Jongen-Lavrencic, Katia Manova-Todorova, Julie Teruya-Feldstein, David E. Avigan, Ruud Delwel, Pier Paolo Pandolfi

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196 Scopus citations

Abstract

MicroRNAs are frequently deregulated in cancer. Here we show that miR-22 is upregulated in myelodysplastic syndrome (MDS) and leukemia and its aberrant expression correlates with poor survival. To explore its role in hematopoietic stem cell function and malignancy, we generated transgenic mice conditionally expressing miR-22 in the hematopoietic compartment. These mice displayed reduced levels of global 5-hydroxymethylcytosine (5-hmC) and increased hematopoietic stem cell self-renewalaccompanied by defective differentiation. Conversely, miR- 22 inhibition blocked proliferation in both mouse and human leukemic cells. Over time, miR-22 transgenic mice developedMDSand hematological malignancies. We also identify TET2 as a key target of miR-22 in this context. Ectopic expression of TET2 suppressed the miR-22-induced phenotypes. Downregulation of TET2 protein also correlated with poor clinical outcomes and miR-22 overexpression in MDS patients. Our results therefore identify miR-22 as a potent proto-oncogene and suggest that aberrations in the miR-22/TET2 regulatory network are common in hematopoietic malignancies. 2013

Original languageEnglish (US)
Pages (from-to)87-101
Number of pages15
JournalCell Stem Cell
Volume13
Issue number1
DOIs
StatePublished - Jul 3 2013

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ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Song, S. J., Ito, K., Ala, U., Kats, L., Webster, K., Sun, S. M., Jongen-Lavrencic, M., Manova-Todorova, K., Teruya-Feldstein, J., Avigan, D. E., Delwel, R., & Pandolfi, P. P. (2013). The oncogenic MicroRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. Cell Stem Cell, 13(1), 87-101. https://doi.org/10.1016/j.stem.2013.06.003