Abstract
In recent years, molecular characterization and management of patients with systemic mastocytosis (SM) have greatly benefited from the application of advanced technologies. Highly sensitive and accurate assays for KIT D816V mutation detection and quantification have allowed the switch to non-invasive peripheral blood testing for patient screening; allele burden has prognostic implications and may be used to monitor therapeutic efficacy. Progress in genetic profiling of KIT, together with the use of next-generation sequencing panels for the characterization of associated gene mutations, have allowed the stratification of patients into three subgroups differing in terms of pathogenesis and prognosis: (i) patients with mast cell-restricted KIT D816V; (ii) patients with multilineage KIT D816V-involvement; (iii) patients with “multi-mutated disease”. Thanks to these findings, new prognostic scoring systems combining clinical and molecular data have been developed. Finally, non-genetic SETD2 histone methyltransferase loss of function has recently been identified in advanced SM. Assessment of SETD2 protein levels and activity might provide prognostic information and has opened new research avenues exploring alternative targeted therapeutic strategies. This review discusses how progress in recent years has rapidly complemented previous knowledge improving the molecular characterization of SM, and how this has the potential to impact on patient diagnosis and management.
Highlights
Mastocytosis is a rare neoplasm characterized by a wide range of clinical manifestations due to excessive proliferation and an increased accumulation of morphologically and immunophenotypically abnormal clonal mast cells (MCs) in different organs and tissues
The results of this study demonstrated that advanced systemic mastocytosis (SM)” (AdvSM) with AHN is a multi-mutated stem cell neoplasm where the acquisition of a KIT D816V as a late genetic event drives phenotype modification towards SM, whereas indolent SM (ISM) and smoldering SM (SSM) seem to not be affected by mutations at the CFU-GM level [66]
KIT D816V has a central role in SM pathogenesis, it can be hypothesized that SETD2 and H3K36Me3 deficiency may cooperate with, and potentiate the effects of KIT constitutive activation to determine the phenotype of AdvSM
Summary
Mastocytosis is a rare neoplasm characterized by a wide range of clinical manifestations due to excessive proliferation and an increased accumulation of morphologically and immunophenotypically abnormal clonal mast cells (MCs) in different organs and tissues. According to the 2016 World Health Organization (WHO) classification, SM includes five major subtypes: indolent SM (ISM), smoldering SM (SSM), SM with an associated clonal hematopoietic non-MC disease (SM-AHN), aggressive SM (ASM), and MC leukemia (MCL) [3,4]. The major diagnostic criterion is the detection, at the level of BM or other extra-cutaneous organs, of dense multifocal infiltrates consisting of cohesively aggregated MCs (>15 MCs). These are often atypical and with a reduced granule content. “B” findings are a measure of disease burden: >30% of MCs in the BM; serum tryptase level >200 ng/mL; signs of dysplasia or proliferation not diagnostic of another hematological malignancy, hepatomegaly or splenomegaly without impairment of organ function. We provide a review of how these advances have integrated previous knowledge and how an improved molecular characterization of the disease is likely to impact on better patient management
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