The imipridone ONC213 targets α-ketoglutarate dehydrogenase to induce mitochondrial stress and suppress oxidative phosphorylation in acute myeloid leukemia.
Yongwei SuJenna L CarterXinyu LiYu FukudaAshley GrayJohn LynchHolly EdwardsJun MaPatrick A SchreinerLisa PolinJuiwanna KushnerSijana H DzinicSteven A BuckShondra M Pruett-MillerKatie Hege HurrishCamenzind G RobinsonXinan QiaoShuang LiuShuangshuang WuGuan WangJing LiJoshua E AllenVarun V PrabhuAaron David SchimmerDhananjay JoshiShiva Kalhor-MonfaredIain D G WatsonRichard MarcellusMethvin B IsaacRima Al-AwarJeffrey W TaubHai LinJohn D SchuetzYubin GePublished in: Cancer research (2024)
Eradication of acute myeloid leukemia (AML) is therapeutically challenging; many patients succumb to AML despite initially responding to conventional treatments. Here, we showed that the imipridone ONC213 elicits potent antileukemia activity in a subset of AML cell lines and primary patient samples, particularly in leukemia stem cells, while producing negligible toxicity in normal hematopoietic cells. ONC213 suppressed mitochondrial respiration and elevated alpha-ketoglutarate by suppressing alpha-ketoglutarate dehydrogenase (α-KGDH) activity. Deletion of OGDH, which encodes α-KGDH, suppressed AML fitness and impaired oxidative phosphorylation, highlighting the key role for α-KGDH inhibition in ONC213-induced death. ONC213 treatment induced a unique mitochondrial stress response and suppressed de novo protein synthesis in AML cells. Additionally, ONC213 reduced translation of MCL-1, which contributed to ONC213-induced apoptosis. Importantly, a patient-derived xenograft from a relapsed AML patient was sensitivity to ONC213 in vivo. Collectively these findings support further development of ONC213 for treating AML.
Keyphrases
- acute myeloid leukemia
- induced apoptosis
- oxidative stress
- allogeneic hematopoietic stem cell transplantation
- endoplasmic reticulum stress
- diabetic rats
- stem cells
- signaling pathway
- end stage renal disease
- case report
- high glucose
- newly diagnosed
- physical activity
- cell cycle arrest
- chronic kidney disease
- ejection fraction
- acute lymphoblastic leukemia
- protein kinase
- peritoneal dialysis
- stress induced
- patient reported outcomes
- helicobacter pylori
- helicobacter pylori infection