Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment.
Aurélie CayeKevin Rouault-PierreMarion StrulluElodie LaineyAnder AbarrategiOdile FenneteauChloé ArfeuilleJennifer OsmanBruno CassinatSabrina PereiraFernando Anjos-AfonsoErin CurrieLinda Ariza-McNaughtonVincent BarlogisJean-Hugues DalleAndré BaruchelChristine ChomienneHélène CavéDominique BonnetPublished in: Leukemia (2019)
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.
Keyphrases
- induced apoptosis
- stem cells
- rna seq
- single cell
- cell cycle arrest
- bone marrow
- acute myeloid leukemia
- end stage renal disease
- endoplasmic reticulum stress
- copy number
- signaling pathway
- newly diagnosed
- chronic kidney disease
- cell proliferation
- cell death
- prognostic factors
- high throughput
- gene expression
- mesenchymal stem cells
- patient reported outcomes
- cell therapy