Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia

Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax +azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profile, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This…

• AC
  American Cancer Society

  Award: 25A5072
• LA
  Leukemia and Lymphoma Society
• BF
  Boettcher Foundation
• EP
  Edward P. Evans Foundation
• UO
  University of Colorado
• LA
  Leukaemia and Lymphoma Research
• NI
  National Institutes of Health

  Awards: 25A5072, R01CA200707, GM008497
• CC
  Cancer Center, University of Colorado

  Award: P30CA046934