Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML.

Chaturvedi A, Araujo Cruz MM, Jyotsana N, Sharma A, Yun H, Görlich K, Wichmann M, Schwarzer A, Preller M, Thol F, Meyer J, Haemmerle R, Struys EA, Jansen EE, Modlich U, Li Z, Sly LM, Geffers R, Lindner R, Manstein DJ, Lehmann U, Krauter J, Ganser A, Heuse

Mutations in the metabolic enzymes isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are frequently found in glioma, acute myeloid leukemia (AML), melanoma, thyroid cancer and chondrosarcoma patients. Mutant IDH produces 2-hydroxyglutarate (2HG), which induces histone- and DNA-hypermethylation through inhibition of epigenetic regulators. We investigated the role of mutant IDH1 using the mouse transplantation assay. Mutant IDH1 alone did not transform hematopoietic cells during 5 months of observation. However, mutant IDH1 greatly accelerated onset of myeloproliferative disease (MPD)-like myeloid leukemia in mice in cooperation with HoxA9 with a mean latency of 83 days compared to cells expressing HoxA9 and wildtype IDH1 or a control vector (167 and 210 days, respectively, P=.001). Mutant IDH1 accelerated cell cycle transition through repression of cyclin-dependent-kinase inhibitors Cdkn2a and Cdkn2b, and activated MAP-kinase signaling. By computational screening, we identified an inhibitor of mutant IDH1, which inhibited mutant IDH1 cells and lowered 2HG levels in vitro, and efficiently blocked colony formation of AML cells from IDH1 mutated patients but not of normal CD34+ bone marrow cells. These data demonstrate that mutant IDH1 has oncogenic activity in vivo and suggest that it is a promising therapeutic target in human AML cells.

Cell Lysis
Mass Spectrometry

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August, 2013



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