Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition.
Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition.
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DOI：
10.1101/gad.226613.113
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发表时间：
2013-09-15
影响因子：
10.5
通讯作者：
Lowe SW
中科院分区：
文献类型：
--
作者：
Chen C;Liu Y;Lu C;Cross JR;Morris JP 4th;Shroff AS;Ward PS;Bradner JE;Thompson C;Lowe SW
异柠檬酸脱氢酶基因IDH 1和IDH 2的体细胞突变经常发生在急性髓细胞白血病（AML）中。Chen等人发现IDH 2突变体与致癌Flt 3或NRas等位基因合作，通过损害骨髓细胞的分化来驱动小鼠中的白血病。抑制含溴结构域蛋白Brd 4触发IDH 2突变AML的快速分化和死亡。这些结果证明了突变IDH 2在白血病发生中的关键作用，并确定了治疗靶向这些癌症的IDH非依赖性策略。异柠檬酸脱氢酶（IDH）基因IDH 1和IDH 2的体细胞突变经常发生在急性髓性白血病（AML）和其他癌症中。这些基因编码产生假定的癌代谢物2-羟基戊二酸（2-HG）的新形态蛋白。尽管通过靶向IDH突变蛋白治疗AML和其他癌症具有前景，但仍不清楚这些突变体如何影响体内肿瘤发展和维持，并且不存在研究IDH 2突变体体内作用的癌症模型。我们发现IDH 2突变体可以与致癌的Flt 3或Nras等位基因合作，通过损害髓系细胞的分化来驱动小鼠白血病。IDH 2的药理学或遗传抑制触发AML细胞的分化和死亡，尽管仅具有延长的IDH 2抑制。相反，抑制含溴结构域蛋白Brd 4触发IDH 2突变AML的快速分化和死亡。我们的研究结果确立了突变IDH 2在白血病发生和肿瘤维持中的关键作用，并确定了治疗这些癌症的IDH独立策略。
Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur frequently in acute myeloid leukemia (AML). Chen et al. find that IDH2 mutants cooperate with oncogenic Flt3 or NRas alleles to drive leukemia in mice by impairing the differentiation of myeloid cells. Inhibiting the bromodomain-containing protein Brd4 triggers rapid differentiation and death of IDH2 mutant AML. These results demonstrate a critical role for mutant IDH2 in leukemogenesis and identify an IDH-independent strategy to therapeutically target these cancers. Somatic mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 occur frequently in acute myeloid leukemia (AML) and other cancers. These genes encode neomorphic proteins that produce the presumed oncometabolite 2-hydroxyglutarate (2-HG). Despite the prospect of treating AML and other cancers by targeting IDH mutant proteins, it remains unclear how these mutants affect tumor development and maintenance in vivo, and no cancer models exist to study the action of IDH2 mutants in vivo. We show that IDH2 mutants can cooperate with oncogenic Flt3 or Nras alleles to drive leukemia in mice by impairing the differentiation of cells of the myeloid lineage. Pharmacologic or genetic inhibition of IDH2 triggers the differentiation and death of AML cells, albeit only with prolonged IDH2 inhibition. In contrast, inhibition of the bromodomain-containing protein Brd4 triggers rapid differentiation and death of IDH2 mutant AML. Our results establish a critical role for mutant IDH2 in leukemogenesis and tumor maintenance and identify an IDH-independent strategy to target these cancers therapeutically.
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64.8
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选择性抑制BET溴结构域。
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64.8
作者：
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通讯作者：
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影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A