Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia.
Mutational cooperativity linked to combinatorial epigenetic gain of function in acute myeloid leukemia.
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DOI：
10.1016/j.ccell.2015.03.009
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发表时间：
2015-04-13
期刊：
影响因子：
50.3
通讯作者：
Levine RL
中科院分区：
文献类型：
--
作者：
Shih AH;Jiang Y;Meydan C;Shank K;Pandey S;Barreyro L;Antony-Debre I;Viale A;Socci N;Sun Y;Robertson A;Cavatore M;de Stanchina E;Hricik T;Rapaport F;Woods B;Wei C;Hatlen M;Baljevic M;Nimer SD;Tallman M;Paietta E;Cimmino L;Aifantis I;Steidl U;Mason C;Melnick A;Levine RL
急性髓性白血病（AML）疾病等位基因的特定组合，包括FLT 3和TET 2突变，赋予不同的生物学特征和不良结局。我们产生了Tet 2和Flt 3突变的小鼠，这导致了完全渗透的致命AML。多能Tet 2 −/−; Flt 3 ITD祖细胞（LSK CD 48 + CD 150 −）在第二次接受者中传播疾病，并且对标准AML化疗和FLT 3靶向治疗无效。Flt 3 ITD突变和Tet 2缺失协同重塑DNA甲基化和基因表达，其程度在单独使用任一突变等位基因时均未见，包括在Gata 2基因座。Gata 2的再表达诱导AML干细胞分化并减弱白血病发生TET 2和FLT 3突变协同诱导AML，确定的白血病干细胞群体的特征在于DNA甲基化和基因表达的位点特异性变化。
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.