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Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations

Singh, Indranil, Fernandez-Perez, Daniel, Sanchez, Pedro Sanchez, Rodriguez-Fraticelli, Alejo E.·2025·Cell Stem Cell
DOI 10.1016/j.stem.2025.01.012
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Abstract

Cancer cells display wide phenotypic variation even across patients with the same mutations. Differences in the cell of origin provide a potential explanation, but traditional assays lack the resolution to distinguish clonally heterogeneous subsets of stem and progenitor cells. To address this challenge, we developed simultaneous tracking of recombinase activation and clonal kinetics (STRACK), a method to trace clonal dynamics and gene expression before and after the acquisition of cancer mutations. Using mouse models, we studied two leukemic mutations, Dnmt3a-R878H and Npm1c, and found that their effect was highly variable across different stem cell states. Specifically, a subset of differentiation-primed stem cells, which normally becomes outcompeted with time, expands with both mutations. Intriguingly, Npm1c mutations reversed the intrinsic bias of the clone of origin, with differentiation-primed stem cells giving rise to more primitive malignant states. Thus, we highlight the relevance of single-cell lineage tracing to unravel early events in cancer evolution and posit that different cellular histories carry distinct cancer phenotypic potential.

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Metadata

Authors
Singh, I., Fernandez-Perez, D., Sanchez, P. S., & Rodriguez-Fraticelli, A. E.
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2025-04
Volume
32
Issue
4
Pages
564-580.e6
ISSN
1934-5909
DOI
10.1016/j.stem.2025.01.012
Cited by
25
References
13
Language
en
Licence
Funders
  • Horizon 2020
  • Agència de Gestió d'Ajuts Universitaris i de Recerca (2017 SGR 1322)
  • Caixabank SA
  • EU Framework Programme for Research and Innovation Marie Skłodowska-Curie Actions (945352, 101109276)
  • Generalitat de Catalunya
  • Institut Ruđer Bošković
  • Universitat de Barcelona
  • Institució Catalana de Recerca i Estudis Avançats
  • Ministerio de Ciencia e Innovación (PID2020-114638RA-I00)
  • HORIZON EUROPE European Research Council (101042992)
  • CRIS Cancer Foundation (PR_EX_2020-24)
  • European Research Council

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Singh, I., Fernandez-Perez, D., Sanchez, P. S., & Rodriguez-Fraticelli, A. E. (2025). Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations. Cell Stem Cell. https://doi.org/10.1016/j.stem.2025.01.012