Molecular and Functional Characterisation of Disease Propagating Stem Cells in Juvenile Myelomonocytic Leukaemia

Juvenile Myelomonocytic Leukemia (JMML) is a rare, poor prognosis childhood leukemia characterized by somatic RAS-activating mutations and secondary mutations in epigenetic modifiers, spliceosome and signaling pathways. The only curative treatment is hematopoietic stem cell transplantation, however, this is associated with very high relapse rates. The cellular hierarchy in JMML has not been previously characterized, with little known about the identity of leukemia stem cells (LSCs), a crucial step towards understanding disease evolution and propagation of relapse. We set out to characterize LSCs in a cohort of JMML patients using samples at diagnosis and post-transplant. Using targeted next generation sequencing (NGS) integrated with index sorting data from single-cell derived colonies, we were able to trace JMML driver mutations to different immunophenotypic compartments, gaining insights into the clonal hierarchy of the disease.