Shih Alan H, Jiang Yanwen, Meydan Cem, Shank Kaitlyn, Pandey Suveg, Barreyro Laura, Antony-Debre Ileana, Viale Agnes, Socci Nicholas, Sun Yongming, Robertson Alexander, Cavatore Magali, de Stanchina Elisa, Hricik Todd, Rapaport Franck, Woods Brittany, Wei Chen, Hatlen Megan, Baljevic Muhamed, Nimer Stephen D, Tallman Martin, Paietta Elisabeth, Cimmino Luisa, Aifantis Iannis, Steidl Ulrich, Mason Chris, Melnick Ari, Levine Ross L
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Institute for Computational Biomedicine and Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA; Department of Medicine/Hematology-Oncology and Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
Cancer Cell. 2015 Apr 13;27(4):502-15. doi: 10.1016/j.ccell.2015.03.009.
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.
急性髓系白血病（AML）疾病等位基因的特定组合，包括FLT3和TET2突变，具有独特的生物学特征和不良预后。我们构建了Tet2和Flt3发生突变的小鼠，这些小鼠会发生完全显性的致死性AML。多能性Tet2(-/-);Flt3(ITD)祖细胞（LSK CD48(+)CD150(-)）可在二次受体中传播疾病，并且对标准AML化疗和FLT3靶向治疗均耐药。Flt3(ITD)突变和Tet2缺失协同重塑DNA甲基化和基因表达，其程度是单独任何一个突变等位基因所未见的，包括在Gata2基因座处。Gata2的重新表达诱导AML干细胞分化并减弱白血病发生。TET2和FLT3突变协同诱导AML，其特定的白血病干细胞群体具有DNA甲基化和基因表达的位点特异性变化特征。
