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

• Published in: International journal of molecular sciences 2020-06, Vol.21 (11), p.3987
• Main Authors: Martelli, Margherita, Monaldi, Cecilia, De Santis, Sara, Bruno, Samantha, Mancini, Manuela, Cavo, Michele, Soverini, Simona
• Format: Article
• Language: English
• Subjects: allele burden; Alleles; Cell Lineage; Cytogenetics; Genetic Variation; Genomics; High-Throughput Nucleotide Sequencing; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humans; KIT tyrosine kinase; Mast Cells - metabolism; Mastocytosis, Systemic - diagnosis; Mastocytosis, Systemic - therapy; Mutation; next-generation sequencing; Phenotype; Prognosis; Proto-Oncogene Proteins c-kit - genetics; Review; SETD2 histone methyltransferase; systemic mastocytosis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21113987

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 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 , 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 D816V; ii) patients with multilineage 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.