Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition

Abstract

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.

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

“…Accumulation of L-2HG slows glycolysis and mitochondrial respiration by reducing the regeneration of NAD +18 . Moreover, hypoxia-induced L-2HG promotes the same repressive chromatin marks that characterize the differentiation blockade of IDH-mutant malignancies 8,17,19 , consistent with the well established association between hypoxic niches and stem cell populations 20 .…”

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations

“…IDH1/2 mutations can be identified in approximately 20% of patients with AML and approximately 5% of patients with MDS (37,38), and can contribute to leukemia via a block in hematopoietic cell differentiation (16,17,23,24,39). We have discovered AG-221, an oral, selective, first-in-class inhibitor of the mutant IDH2 enzyme.…”

“…IDH mutations are also found in premalignant disorders, including myelodysplastic syndromes (MDS), and were shown to drive leukemic transformation in cooperation with other genetic events in IDH-mutant mouse models of AML (23)(24)(25). It is possible that IDH-mutant cells drive clonal hematopoiesis, sustaining a reservoir of stem cells associated with resistance to conventional chemotherapy that needs to be targeted via alternative mechanisms (26)(27)(28).…”

Mutant IDH : A Targetable Driver of Leukemic Phenotypes Linking Metabolism, Epigenetics and Transcriptional Regulation

“…Conversely, a compound transgenic mouse of Flt3-ITD and IDH2m R140Q developed both myeloid and lymphoid acute leukemias [20]. Finally, NrasG12D expression in hematopoietic cells results in a latent myeloproliferative disorder [72]; however, co-expression of IDH2 R140Q or R172K resulted in an acute leukemia [67]. Collectively, these data suggest that the cellular and phenotypic aberrancies resulting from IDHm enzymes are insufficient for oncogenic transformation.…”

“…While this was not associated with global changes in 5mC or histone methylation, IDH2m overexpression resulted in elevated levels of 2-HG production and a global loss of 5hmC. These mice developed a myeloid disorder, however, with some dysplastic features [67]. Interestingly, transplantation of LSK cells overexpressing IDH2 R140Q using a different retroviral vector (MSCV) resulted in a more heterogeneous set of phenotypes.…”