Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment

Caye, Aurélie, Rouault-Pierre, Kevin, Strullu, Marion, Lainey, Elodie, Abarrategi, Ander, Fenneteau, Odile, Arfeuille, Chloé, Osman, Jennifer, Cassinat, Bruno, Pereira, Sabrina, Anjos-Afonso, Fernando ORCID: https://orcid.org/0000-0003-4392-488X, Currie, Erin, Ariza-McNaughton, Linda, Barlogis, Vincent, Dalle, Jean-Hugues, Baruchel, André, Chomienne, Christine, Cavé, Hélène and Bonnet, Dominique 2020. Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment. Leukemia 34 , pp. 1658-1668. 10.1038/s41375-019-0662-y

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Abstract

Juvenile myelomonocytic leukemia (JMML) is a rare aggressive myelodysplastic/myeloproliferative neoplasm of early childhood, initiated by RAS-activating mutations. Genomic analyses have recently described JMML mutational landscape; however, the nature of JMML-propagating cells (JMML-PCs) and the clonal architecture of the disease remained until now elusive. Combining genomic (exome, RNA-seq), Colony forming assay and xenograft studies, we detect the presence of JMML-PCs that faithfully reproduce JMML features including the complex/nonlinear organization of dominant/minor clones, both at diagnosis and relapse. Further integrated analysis also reveals that although the mutations are acquired in hematopoietic stem cells, JMML-PCs are not always restricted to this compartment, highlighting the heterogeneity of the disease during the initiation steps. We show that the hematopoietic stem/progenitor cell phenotype is globally maintained in JMML despite overexpression of CD90/THY-1 in a subset of patients. This study shed new lights into the ontogeny of JMML, and the identity of JMML-PCs, and provides robust models to monitor the disease and test novel therapeutic approaches.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	Springer Nature
ISSN:	0887-6924
Date of First Compliant Deposit:	25 February 2020
Date of Acceptance:	17 November 2019
Last Modified:	30 Jun 2023 12:16
URI:	https://orca.cardiff.ac.uk/id/eprint/129962

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