Metabolic reprogramming by PRDM16 drives cytarabine resistance in acute myeloid leukemia
Acute myeloid leukemia (AML) patients with high PRDM16 expression frequently experience induction failure and have a poor prognosis. However, the molecular mechanisms underlying these clinical features are elusive. We found that murine AML cells transformed by MLL::AF9 fusion and oncogenic short-isoform Prdm16 overexpression (hereafter, MF9/sPrdm16) exhibited resistance to cytarabine (AraC), but not to anthracycline, both in vitro and in vivo. Intriguingly, MF9/sPrdm16 cells displayed a gene expression signature of high oxidative phosphorylation (OxPHOS) and increased mitochondrial respiration. The inhibition of mitochondrial respiration with metformin or tigecycline abrogated AraC resistance in MF9/sPrdm16 cells via an energetic shift toward low OxPHOS status. Furthermore, sPrdm16 upregulated c-Myc and the glutamine transporter Slc1a5, activating TCA cycle and glutaminolysis. Of note, both OxPHOS and MYC-target gene signatures were significantly enriched in AML patient samples with high PRDM16 expression. Together, we showed that PRDM16 overexpression activates mitochondrial respiration through metabolic reprogramming via c-MYC-SLC1A5-Glutaminolysis axis, thereby conferring AraC resistance on AML cells. These results suggest that targeting mitochondrial respiration might be a novel treatment strategy to overcome chemoresistance in AML patients with high PRDM16 expression. Overall design: We first transduced murine bone marrow cells with retroviral MLL::AF9 vector. Subsequently, we transduced murine normal bone marrow cells or MLL::AF9 AML cells with either mock or sPrdm16-expressing retroviral vector. To explore molecular basis of chemoresistance driven by sPrdm16 expression, we performed RNA-seq using these cells.