Single-cell analysis reveals theKITD816V mutation in hematopoietic stem and progenitor cells in systemic mastocytosis [article]

Jennine Grootens, Johanna S Ungerstedt, Maria Ekoff, Elin Rönnberg Höckerlind, Monika Klimkowska, Rose-Marie Amini, Michel Arock, Stina Söderlund, Mattias Mattsson, Gunnar Nilsson, Joakim S Dahlin
2018 bioRxiv   pre-print
Systemic mastocytosis (SM) is a hematological disease characterized by organ infiltration by neoplastic mast cells. Almost all SM patients have a mutation in the gene encoding the tyrosine kinase receptor KIT causing a D816V substitution and autoactivation of the receptor. In this study, we analyzed the occurrence of the D816V mutation during hematopoiesis to evaluate whether this mutation is an early or late event in SM. Using a panel of 9 fluorescently labeled antibodies, 10 different
more » ... ietic progenitor subsets and mature mast cells were identified. The frequencies of the progenitor subsets did not differ between controls and SM patients. Single-cell index sorting and D816V mutation assessment were applied to analyze mast cells and more than 10,000 CD34+bone marrow progenitors from SM patients. We found that in SM 60-99% of the mast cells harbored the mutation, and the mutation could be detected throughout the hematopoietic landscape, from stem cells to more lineage-primed progenitors. However, the occurrence of the mutation in stem and progenitor cells was heterogeneous and varied between patients. Thus, the D816V mutation appears to be an early event in the development of SM but accumulates in the mast cell lineage. In addition, we demonstrate that mast cells originate from an FcϵRI+bone marrow progenitor, and we describe aberrant CD45RA expression on SM mast cells for the first time. Taken together, our findings provide novel insight into hematopoiesis and the occurrence of theKITD816V mutation in SM.
doi:10.1101/394304 fatcat:4xouwuxffbhjvibylcpfpxypai