Unbiased analysis of NUP98-KDM5A-induced murine leukemia reveals phenotypic heterogeneity recapitulating human disease subtypes.

Authors

Marilaine Fournier, Marion Dubuissez, Mathieu Neault, Jean-Sébastien Delisle, Frédérick A Mallette, Heather J Melichar

Published in

Experimental hematology. Pages 104791. Apr 19, 2025. Epub Apr 19, 2025.

Abstract

NUP98-KDM5A (NK5) is an oncogenic fusion protein implicated in the development of several types of acute myeloid leukemia (AML) in humans, including rare pediatric acute megakaryoblastic leukemia (AMKL). NK5 expression in murine hematopoietic progenitor cells can induce AML in mice. However, the limited number of animals and phenotypic markers used in previous studies preclude the full characterization of the AML subtypes that develop. We used NK5-transduced hematopoietic progenitor cells from murine fetal liver to generate a large cohort of mice, assessed the expression of a panel of myeloid markers to characterize the lineage of leukemic blasts by flow cytometry, and used bioinformatic tools to perform an unbiased analysis assessing the extensive mouse-to-mouse heterogeneity in leukemic cellular phenotypes. We were able to identify phenotypically distinct sub-groups among the NK5 leukemias that segregated predominantly based on expression of the AMKL-associated marker CD41. Our results suggest that NK5 expression in fetal liver cells gives rise to heterogenous types of leukemia similar in proportion to that observed in human pediatric patients. The heterogeneity and mixed phenotypes observed might explain the difficulty in accurately diagnosing leukemia in some patients carrying the NK5 fusion. In addition, this approach may enable identification of the molecular or cellular basis of the diverse NK5-driven AML types. TEASER ABSTRACT: NUP98-KDM5A (NK5) gives rise to a variety of leukemia types in human, including rare pediatric AMKL. The development of curative treatments for NK5+ AMKL is hindered by the lack of animal models that recapitulate human disease. Using unbiased clustering of phenotypic data, we confirm that NK5+ leukemia can be modeled in mice and identify a population of NK5+ AMKL-like leukemias in similar proportion to that observed in human patients. The model will enable identification of the molecular mechanisms driving NK5 leukemias as well as the testing of tailored treatment approaches.

PMID:
40258564
Bibliographic data and abstract were imported from PubMed on 22 Apr 2025.

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