RUNX1-ETO and CBFβ-MYH11 converge on aberrant activation of BCAT1 to confer a therapeutic vulnerability in core binding factor-acute myeloid leukemia

Abstract Background: Effective targeted therapy is an unmet clinical need for core binding factor-acute myeloid leukemia (CBF-AML) characterized by RUNX1-ETO and CBFb-MYH11 fusions. However, therapeutically targeting oncogenic fusions involving transcription factors remains challenging. Recent studies point to aberrant amino acid metabolisms as actionable therapeutic targets. Methods: We analyzed the expression of BCAT1 in a large cohort of AML patients and a series of AML cell lines. Altered BCAA metabolism was assessed by metabolic profiling. Transcriptional activation of BCAT1 by RUNX1-ETO and CBFb-MYH11 fusions was determined by ChIP-seq data, luciferase reporter assays, genetic manipulation, and chromatin conformation analysis. Anti-leukemic effects of inhibiting BCAT1 by genetic and pharmaceutical approaches were evaluated both in vitro and in vivo . Results: High expression of BCAT1 was exclusively found in CBF-AML patients and subsequently led to reprogrammed BCAA metabolism. Mechanistically, RUNX1-ETO and CBFb-MYH11 fusion proteins bound to chromatin to activate BCAT1 expression in a similar wild-type RUNX1-dependent manner through rewiring the chromatin conformation at the BCAT1 gene locus. Functionally, BCAT1 inhibition resulted in blunted cell cycle, enhanced apoptosis, and myeloid differentiation of CBF-AML cells in vitro , pointing to critical dependence on BCAA metabolism. Strikingly, in vivo therapeutic effects of inhibiting BCAT1 by its specific inhibitor, Gabapentin, were evidenced by delayed leukemia progression and improved survival using the xenografted mouse model. Conclusions: RUNX1-ETO and CBFβ-MYH11 converge on aberrant activation of BCAT1 , representing a targeted therapeutic opportunity for CBF-AML.