%0 Journal Article
%A Waclawiczek, Alexander
%A Leppä, Aino-Maija
%A Renders, Simon
%A Stumpf, Karolin
%A Reyneri, Cecilia
%A Betz, Barbara
%A Janssen, Maike
%A Shahswar, Rabia
%A Donato, Elisa
%A Karpova, Darja
%A Thiel, Vera
%A Unglaub, Julia M
%A Grabowski, Susanna
%A Gryzik, Stefanie
%A Vierbaum, Lisa
%A Schlenk, Richard
%A Rollig, Christoph
%A Hundemer, Michael
%A Pabst, Caroline
%A Heuser, Michael
%A Raffel, Simon
%A Muller-Tidow, Carsten
%A Sauer, Tim
%A Trumpp, Andreas
%T Combinatorial BCL-2 family expression in Acute Myeloid Leukemia Stem Cells predicts clinical response to Azacitidine/Venetoclax.
%J Cancer discovery
%V 13
%N 6
%@ 2159-8274
%C Philadelphia, Pa.
%M DKFZ-2023-00484
%P 1408-1427
%D 2023
%Z #EA:A010#LA:A010# / 2023 Jun 2;13(6):1408-1427
%X The BCL-2 inhibitor Venetoclax (VEN) in combination with Azacitidine (5-AZA) is currently transforming Acute Myeloid Leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined therapy outcome. LSCs of 5-AZA/VEN refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based 'Mediators-of-Apoptosis-Combinatorial-Score' (MAC-Score) linking the ratio of protein expression of BCL-2, BCL-xL, and MCL-1 in LSCs. MAC-Scoring predicts initial response with a positive predictive-value of >97
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:36892565
%R 10.1158/2159-8290.CD-22-0939
%U https://inrepo02.dkfz.de/record/274189