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Data from: Small molecule OPA1 inhibitors reverse mitochondrial adaptations to overcome therapy resistance in acute myeloid leukemia

Al-Santli, Wafa1; Witkowski, Matthew1; Gritsman, Kira2; Su, Xiaoyang3; Ames, Kristina2; Verma, Amit2; Mattarei, Andrea4; Aifantis, Iannis1; Scorrano, Luca5; Magrin, Federico5; Pellattiero, Anna5; Doshi, Saurav6; Antonoglou, Petros6; Avrampou, Kleopatra1; La Vecchia, Sofia6; Kundu, Tanima6; Glytsou, Christina6

Published Jun 05, 2026 on Dryad. https://doi.org/10.5061/dryad.547d7wmmb

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Jun 05, 2026 version files 5.59 MB

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Abstract

Acute myeloid leukemia (AML) is the most prevalent and deadliest adult leukemia. Its frontline treatment employs the BH3 mimetic Venetoclax to trigger mitochondria-dependent apoptosis. However, drug resistance nearly always develops, calling for therapeutic approaches to circumvent it. Advanced microscopy and genome-wide CRISPRi screen analyses pinpointed mitochondrial adaptations primarily mediated by the master regulator of cristae shape Optic Atrophy 1 (OPA1) as critical for BH3 mimetics resistance. Resistant AML cells upregulate OPA1 to modify their mitochondrial structure and evade apoptosis. MYLS22 and Opitor-0, two specific and non-toxic OPA1 inhibitors, promote apoptotic cristae remodeling and cytochrome c release, synergizing with Venetoclax in AML cells and AML patient-derived xenografts ex vivo and in vivo. Mechanistically, loss of OPA1 renders AML cells dependent on glutamine for oxidative metabolism and sensitizes them to ferroptosis by activating ATF4-regulated integrated stress responses. Overall, our data clarify how OPA1 upregulation allows metabolic flexibility and survival of AML cells and nominates specific OPA1 inhibitors as efficacious tools to overcome Venetoclax resistance in leukemia.