Chaturvedi A, Araujo Cruz M M, Jyotsana N, Sharma A, Goparaju R, Schwarzer A, Görlich K, Schottmann R, Struys E A, Jansen E E, Rohde C, Müller-Tidow C, Geffers R, Göhring G, Ganser A, Thol F, Heuser M
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
Leukemia. 2016 Aug;30(8):1708-15. doi: 10.1038/leu.2016.71. Epub 2016 Apr 11.
Canonical mutations in IDH1 and IDH2 produce high levels of the R-enantiomer of 2-hydroxyglutarate (R-2HG), which is a competitive inhibitor of α-ketoglutarate (αKG)-dependent enzymes and a putative oncometabolite. Mutant IDH1 collaborates with HoxA9 to induce monocytic leukemia in vivo. We used two mouse models and a patient-derived acute myeloid leukemia 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 manner and can drive the expansion of many different leukemic and preleukemic clones that may express wild-type 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.
异柠檬酸脱氢酶1（IDH1）和异柠檬酸脱氢酶2（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，它是α-酮戊二酸（αKG）依赖性酶的竞争性抑制剂，也是一种假定的肿瘤代谢物。突变型IDH1与HoxA9协同作用在体内诱发单核细胞白血病。我们使用了两种小鼠模型和一种患者来源的急性髓系白血病异种移植（PDX）模型，以评估R-2HG、S-2HG和αKG在不依赖突变型IDH1蛋白情况下的体内转化潜力。我们发现，R-2HG而非S-2HG或αKG是体内的一种肿瘤代谢物，它无需突变型IDH1蛋白即可诱导白细胞增多症，并加速小鼠和人类白血病的发病。因此，循环中的R-2HG以旁分泌方式发挥作用，可驱动许多可能表达野生型IDH1的不同白血病和白血病前期克隆的扩增，因此可能是克隆进化和多样性的驱动因素。此外，我们还表明，当细胞内R-2HG水平相当时，突变型IDH1蛋白比单独的R-2HG是更强的致癌基因。因此，我们提出突变型IDH1具有不依赖R-2HG的致癌功能，除了抑制R-2HG的产生外，可能还需要针对这些功能来充分发挥IDH1抑制的治疗潜力。
