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Targeting cell cycle and apoptosis to overcome chemotherapy resistance in acute myeloid leukemia

Victoria Y Ling1,2,3, Jasmin Straube1,2, William Godfrey1

  • 1QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.

Leukemia
|November 18, 2022
PubMed

Insights

Defective cell cycle arrest contributes to chemotherapy resistance in acute myeloid leukemia (AML). Targeting cell cycle or apoptosis synergizes with chemotherapy, improving AML treatment outcomes.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Chemotherapy resistance in acute myeloid leukemia (AML) leads to poor patient outcomes.
  • Clonal evolution is a key driver of resistance in AML.
  • Understanding resistance mechanisms is crucial for developing effective AML therapies.

Purpose of the Study:

  • To investigate genetic factors contributing to doxorubicin and cytarabine (Dox/AraC) resistance in AML.
  • To identify clinically relevant targets for overcoming chemoresistance in AML.
  • To evaluate novel therapeutic combinations for AML treatment.

Main Methods:

  • Genome-wide CRISPR knockout screens were performed in human AML cell lines.
  • Gene expression and survival data from human AML cohorts were analyzed.
  • Synergistic effects of combination therapies were assessed in vitro.

Main Results:

  • Knockouts in AraC metabolism and cell cycle arrest genes (CDKN2A, CHEK2, TP53) conferred Dox/AraC resistance.
  • Reduced CDKN2A expression correlated with inferior survival and was observed at AML relapse.
  • Targeting cell cycle (palbociclib, WM-1119) or apoptosis (venetoclax) synergized with chemotherapy.

Conclusions:

  • Defective cell cycle arrest is a clinically relevant mechanism of chemoresistance in AML.
  • Targeting cell cycle progression or apoptosis can overcome chemoresistance.
  • Novel therapeutic combinations show promise for enhancing AML response and circumventing resistance.

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