Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment
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Aurélie Caye Kevin Rouault-Pierre Marion Strullu Elodie Lainey Ander Abarrategi Odile Fenneteau Chloé Arfeuille Jennifer Osman Bruno Cassinat Sabrina Pereira Fernando Dos Anjos Afonso Erin Currie Linda Ariza-Mcnaughton Vincent Barlogis Jean-Hugues Dalle André Baruchel Christine Chomienne Hélène Cavé Dominique BonnetAbstract
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.
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Journal Leukemia
Volume 34
Issue number 6
Pages 1658-1668
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Publisher website (DOI) 10.1038/s41375-019-0662-y
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Europe PubMed Central 31776464
Pubmed 31776464
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