RT Journal Article
SR Electronic
T1 Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 628479
DO 10.1101/628479
A1 Eleni Louka
A1 Benjamin Povinelli
A1 Alba Rodriguez Meira
A1 Gemma Buck
A1 Neil Ashley
A1 Angela Hamblin
A1 Christopher A.G. Booth
A1 Nikolaos Sousos
A1 Anindita Roy
A1 Natalina Elliott
A1 Deena Iskander
A1 Josu de la Fuente
A1 Nicholas Fordham
A1 Sorcha O’Byrne
A1 Sarah Inglott
A1 Anupama Rao
A1 Irene Roberts
A1 Adam J. Mead
YR 2019
UL http://biorxiv.org/content/early/2019/05/07/628479.abstract
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.