Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate.
Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate.
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DOI：
10.1038/leu.2016.71
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发表时间：
2016-08
期刊：
影响因子：
11.4
通讯作者：
Heuser M
中科院分区：
文献类型：
--
作者：
Chaturvedi A;Araujo Cruz MM;Jyotsana N;Sharma A;Goparaju R;Schwarzer A;Görlich K;Schottmann R;Struys EA;Jansen EE;Rohde C;Müller-Tidow C;Geffers R;Göhring G;Ganser A;Thol F;Heuser M
IDH1和IDH2的典型突变会产生高水平的2-羟基戊二酸（R-2HG）的r -对映体，R-2HG是α kg依赖性酶的竞争性抑制剂，被认为是肿瘤代谢物。突变体IDH1与HoxA9协同在体内诱导单核细胞白血病。我们采用两种小鼠模型和患者源性AML异种移植（PDX）模型来评估独立于IDH1突变蛋白的R-2HG、S-2HG和αKG在体内的转化潜力。我们发现，在体内，R-2HG，而不是S-2HG或αKG，是一种肿瘤代谢物，不需要突变的IDH1蛋白来诱导高白细胞血症和加速小鼠和人类白血病的发生。因此，循环R-2HG以旁分泌方式起作用，可以驱动可能表达野生型IDH1的许多不同的白血病和白血病前期克隆的扩增，因此可以成为克隆进化和多样性的驱动因素。此外，我们发现，当细胞内R-2HG水平达到相当水平时，突变体IDH1蛋白比单独的R-2HG更强。因此，我们提出突变体IDH1的R-2HG独立的致癌功能，除了R-2HG的产生外，可能还需要针对这些功能来开发IDH1抑制的全部治疗潜力。
Canonical mutations in IDH1 and IDH2 produce high levels of the R-enantiomer of 2-hydroxyglutarate (R-2HG), which is a competitive inhibitor of αKG-dependent enzymes and a putative oncometabolite. Mutant IDH1 collaborates with HoxA9 to induce monocytic leukemia in vivo. We employed two mouse models and a patient derived AML xenotransplantation (PDX) model to evaluate the in vivo transforming potential of R-2HG, S-2HG, and αKG independent of the mutant IDH1 protein. We show that R-2HG, but not S-2HG or αKG, is an oncometabolite in vivo that does not require the mutant IDH1 protein to induce hyperleukocytosis and to accelerate the onset of murine and human leukemia. Thus, circulating R-2HG acts in a paracrine fashion and can drive the expansion of many different leukemic and preleukemic clones that may express wildtype IDH1, and therefore can be a driver of clonal evolution and diversity. In addition we show that the mutant IDH1 protein is a stronger oncogene than R-2HG alone when comparable intracellular R-2HG levels are achieved. We therefore propose R-2HG independent oncogenic functions of mutant IDH1 that may need to be targeted in addition to R-2HG production to exploit the full therapeutic potential of IDH1 inhibition.