Journal Article

DKFZ-2026-01114

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Leukemic stem cell subtypes determine venetoclax resistance and therapeutic vulnerabilities in AML.

Waclawiczek, A. (First author)DKFZ* ; Leppä, A.-M.DKFZ* ; Renders, S.DKFZ* ; Bergerweiss, I.DKFZ* ; Stumpf, K.DKFZ* ; Betz, B.DKFZ* ; Gabrowski, S. ; Huang, F. Y.DKFZ* ; Lalioti, M.-E. ; Hempel, B.DKFZ* ; Sohn, M.DKFZ* ; Kuusanmäki, H. ; Thiel, V.DKFZ* ; Unglaub, J. M.DKFZ* ; Shahswar, R. ; Richter, S. ; Janssen, M. ; Karpova, D. ; Donato, E.DKFZ* ; Bonig, H. ; Röllig, C. ; Raffel, S. ; Heuser, M. ; Hundemer, M. ; Kontro, M. ; Eisfeld, A.-K. ; Sauer, T. ; Cabezas-Wallscheid, N. ; Müller-Tidow, C.DKFZ* ; Trumpp, A. (Last author)DKFZ*

2026
Elsevier Amsterdam [u.a.]

Abstract: The BCL-2 inhibitor venetoclax has transformed the treatment of acute myeloid leukemia (AML), but relapse due to resistance of leukemic stem cells (LSCs) remains a major challenge. By molecular and functional profiling of LSCs from >150 patients, we identify four LSC subtypes. These mirror distinct hematopoietic lineage stages, which determine the expression ratio between the venetoclax target BCL-2 and resistance-inducing proteins MCL-1 and BCL-xL (MAC-score). Longitudinal analyses reveal that venetoclax resistance mostly arises in LSCs through plasticity toward a megakaryocytic/erythroid-progenitor (MEP)-LSC state that switches survival dependency from BCL-2 to BCL-xL. In rare cases, mature monocytic/dendritic (MoDe)-LSCs, found within LAMP5+ monocytic AMLs, drive venetoclax resistance. LSC subtyping improves genetic risk stratification and provides subtype-specific therapies: venetoclax-resistant MEP-LSCs respond to BCL-xL inhibitors, whereas MoDe-LSCs are sensitive to MEK1/2 inhibition. Our findings reveal four distinct LSC types with unique vulnerabilities and propose biomarker-guided treatment strategies that complement genetic profiling to overcome venetoclax resistance.

Keyword(s): BCL-2 ; MAC-score ; acute myeloid leukemia ; azacitidine ; chemotherapy ; leukemic stem cells ; personalized medicine ; plasticity ; therapy resistance ; venetoclax

Note: DKFZ-ZMBH Alliance /#EA:A010#LA:A010# / #DKTKZFB26# / #NCTZFB26# / Volume 33, Issue 6, 4 June 2026, Pages 982-999.e8

---

Contributing Institute(s):

1. Stammzellen und Krebs (A010)
2. DKTK HD zentral (HD01)
3. Koordinierungsstelle NCT Heidelberg (HD02)

Research Program(s):

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

Appears in the scientific report 2026

---

Database coverage:
; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 20 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---