Journal Article

DKFZ-2024-02422

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Single-cell multiomics analysis reveals dynamic clonal evolution and targetable phenotypes in acute myeloid leukemia with complex karyotype.

Leppä, A.-M. (First author)DKFZ* ; Grimes, K. ; Jeong, H. ; Huang, F. Y.DKFZ* ; Andrades, A. ; Waclawiczek, A.DKFZ* ; Boch, T. ; Jauch, A. ; Renders, S.DKFZ* ; Stelmach, P.DKFZ* ; Müller-Tidow, C. ; Karpova, D.DKFZ* ; Sohn, M.DKFZ* ; Grünschläger, F.DKFZ* ; Hasenfeld, P. ; Benito Garagorri, E. ; Thiel, V.DKFZ* ; Dolnik, A. ; Rodriguez-Martin, B. ; Bullinger, L. ; Mrózek, K. ; Eisfeld, A.-K. ; Krämer, A.DKFZ* ; Sanders, A. D. ; Korbel, J. (Last author)DKFZ* ; Trumpp, A. (Last author)DKFZ*

2024
Macmillan Publishers Limited, part of Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41588-024-01999-x

Abstract: Chromosomal instability is a major driver of intratumoral heterogeneity (ITH), promoting tumor progression. In the present study, we combined structural variant discovery and nucleosome occupancy profiling with transcriptomic and immunophenotypic changes in single cells to study ITH in complex karyotype acute myeloid leukemia (CK-AML). We observed complex structural variant landscapes within individual cells of patients with CK-AML characterized by linear and circular breakage-fusion-bridge cycles and chromothripsis. We identified three clonal evolution patterns in diagnosis or salvage CK-AML (monoclonal, linear and branched polyclonal), with 75% harboring multiple subclones that frequently displayed ongoing karyotype remodeling. Using patient-derived xenografts, we demonstrated varied clonal evolution of leukemic stem cells (LSCs) and further dissected subclone-specific drug-response profiles to identify LSC-targeting therapies, including BCL-xL inhibition. In paired longitudinal patient samples, we further revealed genetic evolution and cell-type plasticity as mechanisms of disease progression. By dissecting dynamic genomic, phenotypic and functional complexity of CK-AML, our findings offer clinically relevant avenues for characterizing and targeting disease-driving LSCs.

Note: DKFZ-ZMBH Alliance / #EA:A010#LA:A010#LA:B480# / 2024 Dec;56(12):2790-2803

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Contributing Institute(s):

1. A010 Stammzellen und Krebs (A010)
2. KKE Mol. Hämatologie/Onkologie (A360)
3. Mechanismen der genetischen Variation und Datenwissenschaft (B480)
4. DKTK HD zentral (HD01)

Research Program(s):

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

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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