Recent Advances in the Molecular Biology of Systemic Mastocytosis: Implications for Diagnosis, Prognosis, and Therapy

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.

Molecular Background, Clinical Features and Management of Pediatric Mastocytosis: Status 2021

“…Despite clinical and phenotypic differences between pediatric and adult forms of mastocytosis, both are clonal disorders associated with somatic mutations in a considerable number of cases [ 16 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Somatic gain-of-function mutations in the gene KIT result in stem cell factor-independent activation and phosphorylation of KIT, which leads to differentiation of MCs from their hematopoietic stem cells, enhanced MC survival and subsequent accumulation of MCs in various organs [ 1 , 2 , 3 , 22 , 23 , 24 ]. Therefore, activating mutations of KIT are considered to play a crucial role in the pathogenesis of mastocytosis.…”

“…Notably, neither clear phenotype-genotype correlation nor relationship between the mutations and familial vs. sporadic disease was found in two French studies on KIT mutations in the skin of children with mastocytosis [ 16 , 19 ]. Interestingly, some patients with mastocytosis have no molecular alterations within KIT, which suggests that they have alterations in genes other than KIT that affect the clinical presentation of the disease [ 19 , 22 , 27 ].…”

Interrogating the molecular genetics of chronic myeloproliferative malignancies for personalized management in 2021

“…In patients with SM, the identification and quantification of the KIT D816V mutation in hematopoietic stem and progenitor cells, as well as mature mast cells, by highly sensitive (sensitivity <0.01%) and specific assays, such as allele-specific oligonucleotide quantitative PCR and digital droplet PCR, allows an accurate diagnosis. [23][24][25][26] This information is also useful for risk stratification, complementing conventional biomarkers such as serum tryptase level and percentage of bone marrow infiltration by mast cells, and may be used for monitoring patients receiving treatment. More recently, the use of targeted NGS panels for the characterization of associated gene mutations, such as SRSF2, ASXL1 and RUNX1, has improved prognostication and has led to the development of novel prognostic scoring systems to optimize clinical management.…”

Mastocytosis—A Review of Disease Spectrum with Imaging Correlation

“…The cytoplasmic portion comprises the juxtamembrane domain and tyrosine kinase domain which is the site for receptor phosphorylation. When SCF binds the receptor, autophosphorylation of tyrosine kinase occurs and facilitates the transduction process [11,12].…”