Article
Author: Robinson, Camenzind ; Gray, Ashley ; Joshi, Dhananjay ; Buck, Steven A. ; Wu, Shuangshuang ; Schuetz, John D. ; Li, Xinyu ; Pruett-Miller, Shondra M. ; Wang, Guan ; Prabhu, Varun V. ; Isaac, Methvin B. ; Su, Yongwei ; Schreiner, Patrick ; Schimmer, Aaron D. ; Dzinic, Sijana H. ; Fukuda, Yu ; Kalhor-Monfared, Shiva ; Allen, Joshua E. ; Ge, Yubin ; Hege-Hurrish, Katie ; Ma, Jun ; Qiao, Xinan ; Polin, Lisa ; Li, Jing ; Carter, Jenna L. ; Kushner, Juiwanna ; Taub, Jeffrey W. ; Lynch, John ; Marcellus, Richard ; Edwards, Holly ; Al-awar, Rima ; Lin, Hai ; Liu, Shuang ; Watson, Iain D. G.
Abstract: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 α-ketoglutarate by suppressing α-ketoglutarate dehydrogenase (αKGDH) activity. Deletion of OGDH, which encodes αKGDH, suppressed AML fitness and impaired oxidative phosphorylation, highlighting the key role for αKGDH 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 the translation of MCL1, which contributed to ONC213-induced apoptosis. Importantly, a patient-derived xenograft from a relapsed AML patient was sensitive to ONC213 in vivo. Collectively, these findings support further development of ONC213 for treating AML.
Significance::In AML cells, ONC213 suppresses αKGDH, which induces a unique mitochondrial stress response, and reduces MCL1 to decrease oxidative phosphorylation and elicit potent antileukemia activity.See related commentary by Boët and Sarry, p. 950