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<p>Acute myeloid leukemia with mutations in <i>TP53</i> (<i>TP53</i><sup>mut</sup> AML) is fatal with a median survival of 6 months. RNA sequencing on purified AML patient samples showed that <i>TP53</i><sup>mut</sup> AML had higher expression of mevalonate pathway genes. Using novel, isogenic <i>TP53</i><sup>mut</sup> AML cell lines and primary samples, we determined that <i>TP53</i><sup>mut</sup> AML resistance to AML chemotherapy cytarabine (AraC) correlated with increased mevalonate pathway activity, a lower induction of reactive oxygen species (ROS), and a mitochondrial response with increased mitochondrial mass and oxidative phosphorylation. Pretreatment with the statin class of mevalonate pathway inhibitors reversed these effects and chemosensitized <i>TP53</i><sup>mut</sup> AML. The geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway was required for <i>TP53</i><sup>mut</sup> AML chemoresistance. In addition to its role in mitochondria biogenesis, we identified a novel function of GGPP in regulating glutathione for management of AraC-induced ROS. However, statins alone were inadequate to fully reverse chemoresistance in vivo and in a retrospective study of 364 <i>TP53</i><sup>mut</sup> AML patients who received chemotherapy concurrently with a statin. Finally, we identified clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need of <i>TP53</i><sup>mut</sup> AML.</p>

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Chemoresistance of TP53 mutant acute myeloid leukemia requires the mevalonate byproduct, geranylgeranyl pyrophosphate, for induction of an adaptive stress response

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月9日

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  • Sarah J. Skuli,
  • A’ishah Bakayoko,
  • Marisa Kruidenier,
  • Bryan Manning,
  • Paige Pammer,
  • Akmal Salimov,
  • Owen Riley,
  • Gisela Brake-Sillá,
  • Derrick Dopkin,
  • Michael Bowman,
  • Leslie N. Martinez-Gutierrez,
  • Colin C. Anderson,
  • Julie A. Reisz,
  • Roberta Buono,
  • Madhuri Paul,
  • Estelle Saland,
  • Francesca Liccardo,
  • Ann DeVine,
  • Sarah Wong,
  • Jimmy P. Xu,
  • Eva Nee,
  • Ryan Hausler,
  • Steffen Boettcher,
  • Said M. Sebti,
  • Catherine Lai,
  • Kara N. Maxwell,
  • Jean-Emmanuel Sarry,
  • David A. Fruman,
  • Angelo D’Alessandro,
  • Clementina Mesaros,
  • Brian Keith,
  • M. Celeste Simon,
  • Pamela J. Sung,
  • Gerald Wertheim,
  • Nicolas Skuli,
  • Robert L. Bowman,
  • Andrew Matthews,
  • Martin Carroll

摘要

Acute myeloid leukemia with mutations in TP53 (TP53mut AML) is fatal with a median survival of 6 months. RNA sequencing on purified AML patient samples showed that TP53mut AML had higher expression of mevalonate pathway genes. Using novel, isogenic TP53mut AML cell lines and primary samples, we determined that TP53mut AML resistance to AML chemotherapy cytarabine (AraC) correlated with increased mevalonate pathway activity, a lower induction of reactive oxygen species (ROS), and a mitochondrial response with increased mitochondrial mass and oxidative phosphorylation. Pretreatment with the statin class of mevalonate pathway inhibitors reversed these effects and chemosensitized TP53mut AML. The geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway was required for TP53mut AML chemoresistance. In addition to its role in mitochondria biogenesis, we identified a novel function of GGPP in regulating glutathione for management of AraC-induced ROS. However, statins alone were inadequate to fully reverse chemoresistance in vivo and in a retrospective study of 364 TP53mut AML patients who received chemotherapy concurrently with a statin. Finally, we identified clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need of TP53mut AML.