PT  - JOURNAL ARTICLE
AU  - Eleni Louka
AU  - Benjamin Povinelli
AU  - Alba Rodriguez Meira
AU  - Gemma Buck
AU  - Neil Ashley
AU  - Angela Hamblin
AU  - Christopher A.G. Booth
AU  - Nikolaos Sousos
AU  - Anindita Roy
AU  - Natalina Elliott
AU  - Deena Iskander
AU  - Josu de la Fuente
AU  - Nicholas Fordham
AU  - Sorcha O’Byrne
AU  - Sarah Inglott
AU  - Anupama Rao
AU  - Irene Roberts
AU  - Adam J. Mead
TI  - Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia
AID  - 10.1101/628479
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 628479
4099  - http://biorxiv.org/content/early/2019/05/07/628479.short
4100  - http://biorxiv.org/content/early/2019/05/07/628479.full
AB  - Juvenile Myelomonocytic Leukemia (JMML) is a poor prognosis childhood leukemia usually caused by germline or somatic RAS-activating mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA-sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin-CD34+CD38-CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment with RAS-activating mutations as a “first hit”, (2) mutations are acquired with both linear and branching patterns of clonal evolution and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal inter-patient heterogeneity of JMML-LSCs which are present in, but not confined to, the phenotypic HSC compartment. RNA-sequencing of JMML-LSCs reveals upregulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, CD96) paving the way for LSC-directed disease monitoring and therapy in this disease.