Well-differentiated systemic mastocytosis: Genetics, mast cell immunophenotypes, and KIT autophosphorylation

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• Well-differentiated systemic mastocytosis (WDSM) is a rare myeloid neoplasm with an often unknown genetic cause.
• KIT mutations, particularly p.D816V, are common in systemic mastocytosis (SM) but not typically found in WDSM.

Purpose of the Study:

• To investigate novel KIT variants, mast cell (MC) aberrant immunophenotypes, and KIT autophosphorylation patterns in WDSM patients.
• To differentiate WDSM from other forms of SM based on genetic and cellular characteristics.

Main Methods:

• Next-generation sequencing (NGS) for KIT variant identification.
• Mast cell immunophenotyping using flow cytometry.
• Functional analysis of KIT variants via transient transfection and autophosphorylation assays.

Main Results:

• Identified 7 WDSM patients (1.5%) among 454 SM patients; none had KIT p.D816V or p.D816Y mutations.
• Discovered novel germline KIT variants (e.g., p.K509I, p.A533D, p.F681L, p.M541L) in 6/9 WDSM subjects.
• Observed intracellular CD2 and CD25 expression on MCs from WDSM patients, with Class I KIT variants showing enhanced ligand-dependent autophosphorylation.

Conclusions:

• The study doubles the known KIT variants associated with WDSM.
• WDSM is genetically distinct from KIT p.D816V+SM.
• Class I KIT activating mutations correlate with aberrant MC immunophenotypes and the WDSM morphology.