Effect of BCAA free diet plus 5+3 chemotherapy compared to 5+3 chemotherapy alone on gene expression in mouse MLL-AF9 AML cells in vivo
Acute Myeloid Leukemia (AML) commonly relapses after initial chemotherapy response. We assessed metabolic adaptations in chemoresistant cells in vivo before overt relapse, identifying altered branched-chain amino acid (BCAA) levels in patient-derived xenografts (PDX) and immunophenotypically identified leukemia stem cells from AML patients. Notably, this was associated with increased BCAA transporter expression with low BCAA catabolism. Restricting of BCAAs further reduced chemoresistant AML cells but relapse still occurred. Among the persisting cells we found an unexpected increase in protein production. This was accompanied by elevated translation of 2-oxoglutarate-and-iron-dependent oxygenase 1 (OGFOD1), a known ribosomal dioxygenase that adjusts the fidelity of tRNA anticodon pairing with coding mRNA1–3 and upregulates protein synthesis in AML driving disease aggressiveness. Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis and improved animal survival even with chemoresistant AML through regulation of protein synthesis. Leukemic cells can therefore persist despite the stress of chemotherapy and nutrient deprivation through adaptive control of translation while sparing normal hematopoiesis. Targeting OGFOD1 may offer a distinctive, translation modifying means of reducing the chemopersisting cells that drive relapse. Overall design: Mice were fed branched chain amino acid (BCAA) free or standard amino acid (AA) diet to determine effects in gene expression following 5+3 (cytarabine and doxorubicin) chemotherapy