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.

Keywords: KIT tyrosine kinase; SETD2 histone methyltransferase; allele burden; next-generation sequencing; systemic mastocytosis.

Figure 1

Representation of the structure of the KIT receptor, illustrating the known function of its domains and localization of all reported KIT mutations in adult patients with mastocytosis. On the left is shown the structure of the receptor. In the center, the 21 KIT exons and the most frequently identified mutations are reported. Abbreviations: Del, deletion; ECD, extracellular domain; Ins, insertion; ITD, internal tandem duplication; JMD, juxtamembrane domain; TKD, tyrosine kinase domain; PTD, phosphotransferase domain; TMD, transmembrane domain. *: mutation found in around 30% of pediatric patients and in > 80% of all adult patients.

Figure 2

Schematic overview of the localization of the key functional domains of the SETD2 protein and its known roles. SETD2-mediated H3K36 tri-methylation is implicated in several cellular processes including: transcriptional regulation, genomic integrity, regulation of replication, methylation of non-histone targets, alternative splicing, and p53 activation.