Myeloid leukemia cells utilize branched chain keto acids to acquire intrinsic resistance to methotrexate

Abstract

Cancer reprograms cellular metabolism to support and accelerate malignant properties, which is known as cancer metabolism. The cancer metabolism has specific roles in acquiring drug resistance mechanisms in multiple types of cancer tissues. Myeloid leukemia cells deregulate branched chain amino acid (BCAA) metabolism to maintain their proliferation and undifferentiated status, but the contribution of this rewired pathway to drug resistance remains poorly understood. Here, we demonstrate that supplementation with branched chain keto acids (BCKAs), the transamination products of BCAAs, specifically attenuates methotrexate (MTX) toxicity in myeloid leukemia cells, whereas direct BCAA supplementation fails to provide a similar protective effect. Conversely, BCKA supplementation inhibits lymphoid leukemia cells, an effect potentially mediated by the activation of hypoxia-inducible factor 1α (HIF-1α). Gene expression analysis further suggests the involvement of activating transcription factor 5 (ATF5) in the BCKA-mediated rescue from MTX toxicity. Clinically, MTX serves as a standard-of-care treatment for lymphoid malignancies, whereas it typically exhibits limited efficacy against myeloid leukemia. Our results highlight a divergent, lineage-specific response to BCKAs, which may underlie metabolic basis for the intrinsic resistance of myeloid leukemia to MTX.