Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event

To explore the molecular profile and its prognostic implication in systemic mastocytosis (SM), we analyzed the mutation status of granulocyte–macrophage colony-forming progenitor cells (CFU-GM) in patients with KIT D816V + indolent SM (ISM, n =4), smoldering SM (SSM, n =2), aggressive SM (ASM, n =1), SM with associated clonal hematologic non-mast cell lineage disorder (SM-AHNMD, n =5) and ASM-AHNMD ( n =7). All patients with (A)SM-AHNMD ( n =12) carried 1–4 (median 3) additional mutations in 11 genes tested, most frequently TET2 , SRSF2 , ASXL1 , CBL and EZH2 . In multi-mutated (A)SM-AHNMD, KIT D816V + single-cell-derived CFU-GM colonies were identified in 8/12 patients (median 60%, range 0–95). Additional mutations were identified in CFU-GM colonies in all patients, and logical hierarchy analysis indicated that mutations in TET2 , SRSF2 and ASXL1 preceded KIT D816V. In ISM/SSM, no additional mutations were detected and CFU-GM colonies were exclusively KIT D816V − . These data indicate that (a) (A)SM-AHNMD is a multi-mutated neoplasm, (b) mutations in TET2 , SRSF2 or ASXL1 precede KIT D816V in ASM-AHNMD, (c) KIT D816V is thus a phenotype modifier toward SM and (d) KIT D816V or other mutations are rare in CFU-GM colonies of ISM/SSM patients, which might explain at least in part their better prognosis.