American Association for Cancer Research
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Figure S1 from The Imipridone ONC213 Targets α-Ketoglutarate Dehydrogenase to Induce Mitochondrial Stress and Suppress Oxidative Phosphorylation in Acute Myeloid Leukemia

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posted on 2024-04-01, 07:22 authored by Yongwei Su, Jenna L. Carter, Xinyu Li, Yu Fukuda, Ashley Gray, John Lynch, Holly Edwards, Jun Ma, Patrick Schreiner, Lisa Polin, Juiwanna Kushner, Sijana H. Dzinic, Steven A. Buck, Shondra M. Pruett-Miller, Katie Hege-Hurrish, Camenzind Robinson, Xinan Qiao, Shuang Liu, Shuangshuang Wu, Guan Wang, Jing Li, Joshua E. Allen, Varun V. Prabhu, Aaron D. Schimmer, Dhananjay Joshi, Shiva Kalhor-Monfared, Iain D. G. Watson, Richard Marcellus, Methvin B. Isaac, Rima Al-awar, Jeffrey W. Taub, Hai Lin, John D. Schuetz, Yubin Ge

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Funding

Kids Without Cancer

Children's Hospital of Michigan Foundation (CHMF)

U CAN-CER VIVE Foundation (U CAN-CER VIVE)

Ginopolis/Karmanos Endowment

Ring Screw Textron Endowed Chair for Pediatric Cancer Research

Ronald N. Buick Chair in Oncology Research

National Cancer Institute (NCI)

United States Department of Health and Human Services

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American Lebanese Syrian Associated Charities (ALSAC)

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ARTICLE 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. 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

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    Cancer Research

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    Keywords

    Hematological CancersLeukemiasPharmacologyCellular pharmacologyMolecular pharmacologyTranslational Research

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