Recent advances in the understanding of mastocytosis: the role of KIT mutations*

Abstract

Mastocytosis is a heterogeneous disorder characterised by the expansion and accumulation of mast cells in different organs and tissues. Mast cell physiology is closely dependent on activation of the stem cell factor/Kit signalling pathways and accumulating evidences confirm the physiopathological key role of activating KIT mutations (typically D816V) in mastocytosis and their relationship with the clinical manifestations of the disease. This paper reviews the most recent advances in the understanding of the molecular mechanisms associated with KIT mutations in mastocytosis, including recent data about the use of new therapies targeting the Kit molecule and its associated downstream signalling pathways.

An immature immunophenotype of bone marrow mast cells predicts for multilineage D816V KIT mutation in systemic mastocytosis

“…13,14 Overall, these results suggest that in SM, the occurrence of an extended clonal hematopoiesis with multilineage involvement by KIT mutated cells could be associated with an early blockade of MC maturation, leading to more immature BMMC features and a less activated phenotype, in association with an increased MC load. As all ISM s þ cases carry in common an activating KIT mutation, 20 in principle, the mutation itself cannot fully explain such phenotypic differences; further studies are necessary to elucidate whether such maturation blockade is the result of the coexistence of additional genetic and/ or epigenetic events in the D816V þ hematopoietic precursor cell, as previously suggested for polycythemia vera, essential thrombocythemia and primary myelofibrosis cases, which share an identical activating somatic mutation of the JAK2 tyrosine kinase gene (JAK2 V617F ), but display distinct clinico-biological features. 21,22 Alternatively, the KIT mutation could target a different stem or precursor cell in both groups of ISM s þ patients with an increased predisposition of ISM s þ cases with multilineage involvement, to acquire additional genetic events and progression to more aggressive forms of the disease.…”

Hotspot mutations in common oncogenes are infrequent in nasopharyngeal carcinoma

“…In our study, we found KIT K558_V560del, E839K and V559I mutations in three NPC patients. K558_V560del and V559I are juxtamembrane mutations located in exon 11 of KIT oncogene which have been observed in GISTs (43,44) and aggressive systemic mastocytosis (ASM), respectively (44). These two mutants showed spontaneous KIT phosphorylation (45) and could transform IL-3-dependent Ba/F3 cells into IL-3-independent growth in the absence of KIT ligand stem cell factor (SCF) (46).…”

Mastocytosis. Review of the literature and description of clinical cases

“…Классификация ВОЗ определяет 7 подтипов болезни: кож-ный МЦ, индолентный СМЦ, СМЦ, ассоциированный с другим клональным заболеванием системы крови нетучноклеточной природы, агрессивный СМЦ, ТКЛ, тучноклеточная саркома и внекожная мастоцитома [3].…”