TY  - JOUR
AU  - Waclawiczek, Alexander
AU  - Leppä, Aino-Maija
AU  - Renders, Simon
AU  - Stumpf, Karolin
AU  - Reyneri, Cecilia
AU  - Betz, Barbara
AU  - Janssen, Maike
AU  - Shahswar, Rabia
AU  - Donato, Elisa
AU  - Karpova, Darja
AU  - Thiel, Vera
AU  - Unglaub, Julia M
AU  - Grabowski, Susanna
AU  - Gryzik, Stefanie
AU  - Vierbaum, Lisa
AU  - Schlenk, Richard
AU  - Rollig, Christoph
AU  - Hundemer, Michael
AU  - Pabst, Caroline
AU  - Heuser, Michael
AU  - Raffel, Simon
AU  - Muller-Tidow, Carsten
AU  - Sauer, Tim
AU  - Trumpp, Andreas
TI  - Combinatorial BCL-2 family expression in Acute Myeloid Leukemia Stem Cells predicts clinical response to Azacitidine/Venetoclax.
JO  - Cancer discovery
VL  - 13
IS  - 6
SN  - 2159-8274
CY  - Philadelphia, Pa.
M1  - DKFZ-2023-00484
SP  - 1408-1427
PY  - 2023
N1  - #EA:A010#LA:A010# / 2023 Jun 2;13(6):1408-1427
AB  - 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
LB  - PUB:(DE-HGF)16
C6  - pmid:36892565
DO  - DOI:10.1158/2159-8290.CD-22-0939
UR  - https://inrepo02.dkfz.de/record/274189
ER  -