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

Authors :
Craig T. Jordan
Clayton A. Smith
Michael R. Savona
Haley E. Ramsey
Jonathan A. Gutman
Angelo D'Alessandro
Travis Nemkov
John M. Ashton
Jason R. Myers
Andrew Hammes
Diana Abbott
Jeffrey Schowinsky
Jessica Ponder
Nabilah Khan
Biniam Adane
Courtney L. Jones
Anna Krug
Haobin Ye
Amanda Winters
Anagha Inguva
Maria L. Amaya
James C. Costello
Jihye Kim
Ryan M. Sheridan
Austin E. Gillen
Kent A. Riemondy
Rui Fu
Mohammad Minhajuddin
Brett M. Stevens
Annika Gustafson
Daniel A. Pollyea
Shanshan Pei
Publication Year :
2023
Publisher :
American Association for Cancer Research (AACR), 2023.

Abstract

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.Significance: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.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........459448356d6d6a3954afc463053a8909
Full Text :
https://doi.org/10.1158/2159-8290.c.6547874.v1