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


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(-/-);Flt3(ITD) progenitors (LSK CD48(+)CD150(-)) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3(ITD) 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.

DOI: 10.1016/j.ccell.2015.03.009

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@article{Shih2015MutationalCL, title={Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia.}, author={Alan H Shih and Yanwen Jiang and Cem Meydan and Kaitlyn Shank and Suveg Pandey and Laura Barreyro and Ileana Antony-Debre and Agnes Viale and Nicholas Socci and Yongming Sun and Alexander Robertson and Magali Cavatore and Elisa de Stanchina and Todd Hricik and Franck Rapaport and Brittany Woods and Chen Wei and Megan Hatlen and Muhamed Baljevic and Stephen D Nimer and Martin Tallman and Elisabeth Paietta and Luisa Cimmino and Iannis Aifantis and Ulrich Steidl and Chris Mason and Ari Melnick and Ross L Levine}, journal={Cancer cell}, year={2015}, volume={27 4}, pages={502-15} }