Journal Article

DKFZ-2023-00484

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Combinatorial BCL-2 family expression in Acute Myeloid Leukemia Stem Cells predicts clinical response to Azacitidine/Venetoclax.

Waclawiczek, A. (First author)DKFZ* ; Leppä, A.-M. (First author)DKFZ* ; Renders, S. (First author)DKFZ* ; Stumpf, K.DKFZ* ; Reyneri, C.DKFZ* ; Betz, B.DKFZ* ; Janssen, M. ; Shahswar, R. ; Donato, E.DKFZ* ; Karpova, D.DKFZ* ; Thiel, V.DKFZ* ; Unglaub, J. M. ; Grabowski, S. ; Gryzik, S. ; Vierbaum, L. ; Schlenk, R.DKFZ* ; Rollig, C. ; Hundemer, M. ; Pabst, C. ; Heuser, M. ; Raffel, S. ; Muller-Tidow, C. ; Sauer, T. ; Trumpp, A. (Last author)DKFZ*

2023
Philadelphia, Pa.

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Please use a persistent id in citations: doi:10.1158/2159-8290.CD-22-0939

Abstract: 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% associated to increased event-free survival. In summary, combinatorial levels of BCL-2-family members in AML-LSCs are a key denominator of response and MAC-Scoring reliably predicts patient response to 5-AZA/VEN.

Note: #EA:A010#LA:A010# / 2023 Jun 2;13(6):1408-1427

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Contributing Institute(s):

1. A010 Stammzellen und Krebs (A010)
2. DKTK HD zentral (HD01)
3. Klinische Studienzentrale (W010)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 25 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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