Journal Article

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

Bonnet, Dominique, Lainey Elodie, Anjos-Afonso, Fernando, Cassinat Bruno, Ariza-McNaughton, Linda, Caye Aurélie, Pereira, Sabrina, Fenneteau Odile, Barlogis Vincent, Rouault-Pierre, Kevin, Osman, Jennifer, Ander, Abarrategi, Currie, Erin, Chomienne, Christine, Cavé Hélène, Arfeuille Chloé, Strullu Marion, Jean-Hugues, Dalle, Baruchel André

2020

Overview

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.

• Publisher: Nature Publishing Group
• Subject: CD90 antigen / Children / Genomic analysis / Hematopoietic stem cells / Heterogeneity / Leukemia / Mutation / Myelomonocytic leukemia / Ontogeny / Phenotypes / Progenitor cells / Ribonucleic acid / RNA / Stem cells / Xenografts / Xenotransplantation