Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia

Alan H. Shih, Yanwen Jiang, Cem Meydan, Kaitlyn Shank, Suveg Pandey, Laura Barreyro, Ileana Antony-Debre, Agnes Viale, Nicholas Socci, Yongming Sun, Alexander Robertson, Magali Cavatore, Elisa deStanchina, Todd Hricik, Franck Rapaport, Brittany Woods, Chen Wei, Megan Hatlen, Muhamed Baljevic, Stephen D. NimerMartin Tallman, Elisabeth Paietta, Luisa Cimmino, Iannis Aifantis, Ulrich Steidl, Chris Mason, Ari Melnick, Ross L. Levine

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3, which resulted in fully penetrant, lethal AML. Multipotent Tet2-/-;Flt3ITD progenitors (LSK CD48+CD150-) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3ITD mutations and Tet2 loss cooperatively remodeled DNA methylation and gene expression to an extent not seen with either mutant allele alone, including at the Gata2 locus. Re-expression of Gata2 induced differentiation in AML stem cells and attenuated leukemogenesis. TET2 and FLT3 mutations cooperatively induce AML, with a defined leukemia stem cell population characterized by site-specific changes in DNA methylation and gene expression.

Original languageEnglish (US)
Pages (from-to)502-515
Number of pages14
JournalCancer Cell
Volume27
Issue number4
DOIs
StatePublished - Apr 13 2015

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Shih, A. H., Jiang, Y., Meydan, C., Shank, K., Pandey, S., Barreyro, L., Antony-Debre, I., Viale, A., Socci, N., Sun, Y., Robertson, A., Cavatore, M., deStanchina, E., Hricik, T., Rapaport, F., Woods, B., Wei, C., Hatlen, M., Baljevic, M., ... Levine, R. L. (2015). Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia. Cancer Cell, 27(4), 502-515. https://doi.org/10.1016/j.ccell.2015.03.009