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<p>MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes harboring <i>KMT2A</i> rearrangements (<i>KMT2A</i>-r). Clinical trials involving patients with hematological malignancies treated with MCL-1 inhibitor monotherapy have been hampered by dose-limiting toxicity and poor response rates. Therefore, we sought to identify combinatorial treatment approaches to enhance the efficacy of MCL-1 inhibitors with the goal of improving response rates and limiting toxicities. Here, we report the inhibition of electron transport chain (ETC) complex I (CI) function as a synthetic lethal partner for MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces the viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML, indicating the preclinical potential for this combinatorial therapy. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML. Mechanistically, we reveal that CI inhibition induces the activation of the integrated stress response, resulting in ATF4 activation downstream of the eIF2α kinase, HRI (Heme-regulated inhibitor). HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with <i>KMT2A</i>-r AML.</p>

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Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月25日

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  • Lauren Brakefield-Laird,
  • Amit Budhraja,
  • Peter M. Hall,
  • Dixie Brewington,
  • Jamila Moore,
  • Josi Lott,
  • Yonghui Ni,
  • Dennis Voronin,
  • Oliver Grant-Chapman,
  • Tresor O. Mukiza,
  • Tristen Wright,
  • Yong-Dong Wang,
  • Sandi Radko-Juettner,
  • Shondra M. Pruett-Miller,
  • Stanley Pounds,
  • Peter Vogel,
  • Joseph T. Opferman

摘要

MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes harboring KMT2A rearrangements (KMT2A-r). Clinical trials involving patients with hematological malignancies treated with MCL-1 inhibitor monotherapy have been hampered by dose-limiting toxicity and poor response rates. Therefore, we sought to identify combinatorial treatment approaches to enhance the efficacy of MCL-1 inhibitors with the goal of improving response rates and limiting toxicities. Here, we report the inhibition of electron transport chain (ETC) complex I (CI) function as a synthetic lethal partner for MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces the viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML, indicating the preclinical potential for this combinatorial therapy. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML. Mechanistically, we reveal that CI inhibition induces the activation of the integrated stress response, resulting in ATF4 activation downstream of the eIF2α kinase, HRI (Heme-regulated inhibitor). HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.