| Literature DB >> 25873173 |
Alan H Shih1, Yanwen Jiang2, Cem Meydan3, Kaitlyn Shank4, Suveg Pandey4, Laura Barreyro5, Ileana Antony-Debre5, Agnes Viale6, Nicholas Socci7, Yongming Sun8, Alexander Robertson8, Magali Cavatore6, Elisa de Stanchina9, Todd Hricik4, Franck Rapaport4, Brittany Woods4, Chen Wei4, Megan Hatlen4, Muhamed Baljevic4, Stephen D Nimer10, Martin Tallman11, Elisabeth Paietta12, Luisa Cimmino13, Iannis Aifantis13, Ulrich Steidl5, Chris Mason3, Ari Melnick14, Ross L Levine15.
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(-/-);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.Entities:
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Year: 2015 PMID： 25873173 PMCID： PMC4518555 DOI： 10.1016/j.ccell.2015.03.009
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743