Germline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia.

The interaction of germline variation and somatic cancer driver mutations is under-investigated. Here we describe the genomic mitochondrial landscape in adult acute myeloid leukaemia (AML) and show that rare variants affecting the nuclear- and mitochondrially-encoded complex I genes show near-mutual exclusivity with somatic driver mutations affecting isocitrate dehydrogenase 1 (IDH1), but not IDH2 suggesting a unique epistatic relationship. Whereas AML cells with rare complex I variants or mutations in IDH1 or IDH2 all display attenuated mitochondrial respiration, heightened sensitivity to complex I inhibitors including the clinical-grade inhibitor, IACS-010759, is observed only for IDH1-mutant AML. Furthermore, IDH1 mutant blasts that are resistant to the IDH1-mutant inhibitor, ivosidenib, retain sensitivity to complex I inhibition. We propose that the IDH1 mutation limits the flexibility for citrate utilization in the presence of impaired complex I activity to a degree that is not apparent in IDH2 mutant cells, exposing a mutation-specific metabolic vulnerability. This reduced metabolic plasticity explains the epistatic relationship between the germline complex I variants and oncogenic IDH1 mutation underscoring the utility of genomic data in revealing metabolic vulnerabilities with implications for therapy.

Interleukin-3-mediated regulation of ß-catenin in myeloid transformation and acute myeloid leukemia.

Aberrant activation of ß-catenin is a common event in AML and is an independent predictor of poor prognosis. Although increased ß-catenin signaling in AML has been associated with oncogenic translocation products and activating mutations in the FLT3R, the mechanisms that activate ß-catenin in AML more broadly are still unclear. Here, we describe a novel link between IL-3 signaling and the regulation of ß-catenin in myeloid transformation and AML. In a murine model of HoxB8 and IL-3 cooperation, we show that ß-catenin protein levels are modulated by IL-3 and that Cre-induced deletion of ß-catenin abolishes IL-3-dependent growth and colony formation. In IL-3-dependent leukemic TF-1.8 cells, we observed increased ß-catenin protein levels and nuclear localization in response to IL-3, and this correlated with transcriptional induction of ß-catenin target genes. Furthermore, IL-3 promoted ß-catenin accumulation in a subset of AML patient samples, and gene-expression profiling of these cells revealed induction of WNT/ß-catenin and TCF4 gene signatures in an IL-3-dependent manner. This study is the first to link ß-catenin activation to IL-3 and suggests that targeting IL-3 signaling may be an effective approach for the inhibition of ß-catenin activity in some patients with AML.