American Association for Cancer Research
21598290cd190710-sup-224317_3_supp_6024348_q44rxx.xlsx (35.75 kB)

Supplementary Tables S1-S6 from Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia

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posted on 2023-04-03, 22:24 authored by Shanshan Pei, Daniel A. Pollyea, Annika Gustafson, Brett M. Stevens, Mohammad Minhajuddin, Rui Fu, Kent A. Riemondy, Austin E. Gillen, Ryan M. Sheridan, Jihye Kim, James C. Costello, Maria L. Amaya, Anagha Inguva, Amanda Winters, Haobin Ye, Anna Krug, Courtney L. Jones, Biniam Adane, Nabilah Khan, Jessica Ponder, Jeffrey Schowinsky, Diana Abbott, Andrew Hammes, Jason R. Myers, John M. Ashton, Travis Nemkov, Angelo D'Alessandro, Jonathan A. Gutman, Haley E. Ramsey, Michael R. Savona, Clayton A. Smith, Craig T. Jordan

Supplementary Tables S1-S6 describing patient characteristics, gene lists, LSC signatures, and reagents.



University of Colorado

Department of Medicine Outstanding Early Career Scholar Program

Leukaemia and Lymphoma Research

E.P. Evans Foundation

Biff Ruttenberg Foundation

Boettcher Foundation

Leukemia and Lymphoma Society

American Cancer Society

University of Colorado Cancer Center



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 differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these findings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis. Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.