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Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis
Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
Karolinska Inst, Dept Med Huddinge, S-14186 Stockholm, Sweden;Karolinska Univ Hosp, Hematol Ctr, S-17176 Stockholm, Sweden.
Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 43, p. 150-158Article in journal (Refereed) Published
Abstract [en]

Background: Systemic mastocytosis (SM) is a haematological disease characterised 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. Mast cells and CD34(+) haematopoietic progenitors can carry the mutation: however, in which progenitor cell subset the mutation arises is unknown. We aimed to investigate the distribution of the D816V mutation in single mast cells and single haematopoietic stem and progenitor cells.

Methods: Fluorescence-activated single-cell index sorting and KIT D816V mutation assessment were applied to analyse mast cells and >10,000 CD34(+) bone marrow progenitors across 10 haematopoietic progenitor subsets. In vitro assays verified cell-forming potential.

Findings: We found that in SM 60-99% of the mast cells harboured the KIT D816V mutation. Despite increased frequencies of mast cells in SM patients compared with control subjects, the haematopoietic progenitor subset frequencies were comparable. Nevertheless, the mutation could be detected throughout the haematopoietic landscape of SM patients, from haematopoietic stem cells to more lineage-primed progenitors. In addition, we demonstrate that Fc epsilon RI+ bone marrow progenitors exhibit mast cell-forming potential, and we describe aberrant CD45RA expression on SM mast cells for the first time.

Interpretation: The KIT D816V mutation arises in early haematopoietic stem and progenitor cells and the mutation frequency is approaching 100% in mature mast cells, which express the aberrant marker CD45RA.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2019. Vol. 43, p. 150-158
Keywords [en]
Systemic Mastocytosis, Single-cell, Mast cell, Mast cell progenitor, CD45RA, Haematopoiesis, Haematopoietic stem cells, KIT D816V
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-387962DOI: 10.1016/j.ebiom.2019.03.089ISI: 000470091600028PubMedID: 30975542OAI: oai:DiVA.org:uu-387962DiVA, id: diva2:1331909
Funder
Swedish Research CouncilSwedish Cancer SocietyThe Cancer Research Funds of RadiumhemmetMagnus Bergvall FoundationTore Nilsons Stiftelse för medicinsk forskningStockholm County CouncilAvailable from: 2019-06-27 Created: 2019-06-27 Last updated: 2019-06-27Bibliographically approved

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