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<p>Outcomes for pediatric acute myeloid leukemia (AML) have improved significantly in recent years. However, relapsed and refractory disease remains a significant problem. The chemotherapy burden experienced by these patients makes the translational development of non-genotoxic experimental therapies attractive. We previously reported that the anti-helminth drug mebendazole induces degradation of the transcription factor MYB and has potent anti-AML activity. In the present study, we use CRISPR drop-out screening to identify genes encoding the proapoptotic regulators BAK and NOXA as hits conferring resistance to mebendazole activity in AML cells. Conversely, targeting MCL1 with a BH3-mimetic significantly enhanced the anti-AML activity of mebendazole in both AML cell lines in vitro and pediatric patient-derived xenograft (PDX) AML cells ex vivo. Treatment of mice transplanted with THP-1 AML cells or aggressive infant PDX AML cells with this drug combination significantly impaired disease progression in vivo. Our data indicate that mebendazole-induced MYB degradation in combination with MCL1 targeting is a novel non-genotoxic therapeutic strategy for pediatric AML.</p>

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MCL1 inhibition to enhance the efficacy of MYB targeting in pediatric acute myeloid leukemia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月13日

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  • Alexia Tsakaneli,
  • Noelia Che,
  • Clemence Virely,
  • Bryony McCord,
  • Luca Gasparoli,
  • Aerin Loe,
  • Kent Fung,
  • Olivia Ciampa,
  • Nuriye Meryem Alver,
  • Qingyin Li,
  • Jack Bartram,
  • David O’Connor,
  • Marc Mansour,
  • Owen Williams

摘要

Outcomes for pediatric acute myeloid leukemia (AML) have improved significantly in recent years. However, relapsed and refractory disease remains a significant problem. The chemotherapy burden experienced by these patients makes the translational development of non-genotoxic experimental therapies attractive. We previously reported that the anti-helminth drug mebendazole induces degradation of the transcription factor MYB and has potent anti-AML activity. In the present study, we use CRISPR drop-out screening to identify genes encoding the proapoptotic regulators BAK and NOXA as hits conferring resistance to mebendazole activity in AML cells. Conversely, targeting MCL1 with a BH3-mimetic significantly enhanced the anti-AML activity of mebendazole in both AML cell lines in vitro and pediatric patient-derived xenograft (PDX) AML cells ex vivo. Treatment of mice transplanted with THP-1 AML cells or aggressive infant PDX AML cells with this drug combination significantly impaired disease progression in vivo. Our data indicate that mebendazole-induced MYB degradation in combination with MCL1 targeting is a novel non-genotoxic therapeutic strategy for pediatric AML.