Major finding: Mutant IDH1 cooperates with HOXA9 to induce myeloproliferative disease/monocytic leukemia.
Approach: An in silico screen identified an inhibitor of mutant IDH1 that specifically killed primary AML cells.
Impact: Mutant IDH1 can promote leukemogenesis in mice and may be targetable in human AML.
Isocitrate dehydrogenase 1 (IDH1) mutations that result in the neomorphic conversion of α-ketoglutarate to R-2-hydroxyglutarate (R-2HG) are common in human acute myeloid leukemias (AML). Accumulation of R-2HG inhibits α-ketoglutarate–dependent enzymes such as DNA methyltransferases and histone demethylases, and expression of mutant IDH1 in mice has been associated with epigenetic alterations and hematopoietic progenitor cell expansion. However, it is not clear that mutant IDH1 has leukemogenic activity in vivo, as mutant IDH1 knock-in mice do not develop leukemia. Hypothesizing that mutant IDH1 might require cooperation with other oncogenes to induce leukemia, Chaturvedi and colleagues compared gene expression profiles of IDH1-mutant and IDH1–wild-type AML and noted that HOXA9 was the most overexpressed HOX gene in patients with IDH1-mutant AML. Expression of mutant IDH1 in Hoxa9-immortalized bone marrow cells dramatically decreased the survival of recipient mice, leading to a myeloproliferative-like disease with features of monocytic leukemia with a short latency. Mutant IDH1 expression promoted cell-cycle progression in association with increased MAPK signaling, but IDH1-mutant cells were refractory to inhibitors of this pathway. To identify mutant IDH1-selective inhibitors, the authors performed an in silico screen and found one compound predicted to bind the isocitrate-binding pocket of mutant IDH1. This compound, called HMS-101, specifically reduced intracellular R-2HG levels and viability of Hoxa9-immortalized cells expressing mutant IDH1. Moreover, HMS-101 induced apoptosis and prevented colony formation of bone marrow cells isolated from patients with IDH1-mutant AML, but not normal bone marrow cells isolated from healthy donors. Collectively, these findings establish that mutant IDH1 can cooperate with other oncogenes to drive leukemogenesis in vivo and suggest that mutant IDH1 may be safely and effectively targeted in AML.
- ©2013 American Association for Cancer Research.
Volume 3, Issue 10
