Variable presence of KIT^D816V in clonal haematological non‐mast cell lineage diseases associated with systemic mastocytosis (SM–AHNMD)

Abstract

In a substantial number of patients with systemic mastocytosis (SM), an associated clonal haematological non-mast cell lineage disease (AHNMD) is detectable. Although most of these patients display KIT mutations, especially KIT(D816V), little is known about their exact frequency and their distribution in AHNMD subtypes. We examined 48 patients with SM-AHNMD for the presence of mutant KIT in the SM and AHNMD components of the disease. Mast cells and AHNMD cells were obtained from immunostained bone marrow sections by laser microdissection and examined by melting point analysis of nested-PCR products. KIT(D816V) was found in AHNMD cells in the vast majority of patients with SM-chronic myelomonocytic leukaemia (CMML, 89%). Unexpectedly, KIT(D816V) was far less frequently detectable in AHNMD cells in patients with SM-myeloproliferative neoplasm (MPN, 20%) and SM-acute myeloid leukaemia (AML, 30%). None of the patients with lymphoproliferative AHNMDs displayed KIT codon 816 mutations in AHNMD cells (0/8). In FIP1L1/PDGFRA-positive chronic eosinophilic leukaemia (CEL), neither the SM nor the CEL component of the disease exhibited the KIT mutation. Our findings demonstrate that KIT codon 816 mutations are variably present in AHNMD cells in patients with SM-AHNMD, depending on the subtype of AHNMD. The high frequency of KIT(D816V) in neoplastic mast cells and leukaemic myelomonocytic cells in SM-CMML may point to a common precursor in these patients, and may have implications for the biology of the disease and the development of KIT-targeting therapies.

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

“…The frequency of involvement of non-MC lineages (generally myeloid, but occasionally lymphoid lineages) by KITD816V appears to be greater in cases of ASM or MCL, as compared with ISM [29]. In contrast, KITD816V is variably present in cells representing the second hematological neoplasm in SM with associated clonal hematological non-mast cell lineage disease (SM-AHNMD) cases, depending upon the particular AHNMD subtype (CMML > MPN, AML > lymphoid neoplasms) [67]. Attempts at validating the WHO diagnostic criteria reveal that 20% of ISM patients lack mast cell clusters in the BM and 30% exhibit a serum tryptase level lower than 20 ng/mL [68].…”

Aberrant expression of CD30 in neoplastic mast cells in high-grade mastocytosis

“…37,38 The human mast cell leukemia cell line HMC-1.2, which is known to display the KIT mutation D816V, served as a positive control. 21 HMC-1 cells were kindly provided by Dr Butterfield of the Mayo Clinic, Rochester, MN, USA.…”

Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2/ASXL1/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis

“…6,7 The multi-lineage expansion by KIT D816V and the KIT D816V allele burden (AB) have an important impact on disease phenotype and prognosis. 6,[8][9][10] Furthermore, the presence and number of molecular aberrations, e.g. in SRSF2, ASXL, or RUNX1 (S/A/R gene panel), have a strong adverse impact on disease phenotype and OS in patients with advSM.. 9,11 One of several WHO criteria to classify SM includes enlargement of visceral organs, e.g.…”