Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia

• DOI: 10.1084/jem.20180853
• Publication Date: 2021-01-13T23:04:38Z
• Authors: Eleni Louka; Benjamin Povinelli; Alba Rodriguez-Meira; Gemma Buck; Wei Xiong Wen; Guanlin Wang; Nikolaos Sousos; Neil Ashley; Angela Hamblin; Christopher A.G. ...; Anindita Roy; Natalina Elliott; Deena Iskander; Josu de la Fuente; Nicholas Fordham; Sorcha O’Byrne; Sarah Inglott; Ruggiero Norfo; Mariolina Salio; Supat Thongjuea; Anupama Rao; Irene Roberts; Adam J. Mead
• Keywords: Juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood usually caused by RAS-pathway mutations. The cellular hierarchy in JMML poorly characterized, including the identity of stem cells (LSCs). FACS and single-cell RNA sequencing reveal marked heterogeneity hematopoietic stem/progenitor (HSPCs), an aberrant Lin−CD34+CD38−CD90+CD45RA+ population. Single-cell HSPC index-sorting clonogenic assays show that (1) all somatic mutations can be backtracked to phenotypic HSC compartment, with as “first hit,” (2) are acquired both linear branching patterns clonal evolution, (3) mutant HSPCs present after allogeneic transplant before molecular/clinical evidence relapse. Stem cell interpatient LSCs, which in, but not confined to, compartment. LSC reveals up-regulation fetal genes (HLF, MEIS1, CNN3, VNN2, HMGA2) candidate therapeutic targets/biomarkers (MTOR, SLC2A1, CD96), paving way for LSC-directed disease monitoring therapy this disease.