KIT D816V–mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression

Abstract

Key Points• Acquisition of the KIT D816V mutation in an early pluripotent progenitor cell confers ISM cases a greater risk for disease progression.• Despite the early acquisition of the KIT mutation, onset of clinical symptoms of ISM is often delayed to middle adulthood.Multilineage involvement of bone marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult indolent systemic mastocytosis (ISM) patients in association with a poorer prognosis. Here, we investigated the potential involvement of BM mesenchymal stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease progression and outcome. This mutation was investigated in highly purified BM MSCs and other BM cell populations from 83 ISM patients followed for a median of 116 months. KIT D816V-mutated MSCs were detected in 22 of 83 cases. All MSCmutated patients had multilineage KIT mutation (100% vs 30%, P 5 .0001) and they more frequently showed involvement of lymphoid plus myeloid BM cells (59% vs 22%; P 5 .03) and a polyclonal pattern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P 5 .01) vs other multilineage ISM cases. Moreover, presence of KIT-mutated MSCs was associated with more advanced disease features, a greater rate of disease progression (50% vs 17%; P 5 .04), and a shorter progression-free survival (P £ .003). Overall, these results support the notion that ISM patients with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, prior to differentiation into MSCs and hematopoietic precursor cells, before the X-chromosome inactivation process occurs. From a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a significantly greater risk for disease progression and a poorer outcome. (Blood. 2016;127(6):761-768)

Clinical presentation and management practice of systemic mastocytosis. A survey on 460 Italian patients

“…In particular, ASM and SM-AHNMD were risk factors for reduced survival, suggesting that an important goal of further studies is to identify risk variables predicting for early disease progression and shortened survival. At this regard, recent findings indicate that variables not currently used in clinical practice, such as quantification of the expression of cKITD816V mutation in different BM cell lineages [29] and in bone marrow mesenchymal stem cells [30], the cKITD816V allele burden [31], the expression of CD30 in neoplastic mast cells [32] and mutations in other genes including TET2, ASXL1, SRSF2, RUNX1 and CBL [33], all have prognostic value that deserves careful scrutiny. We also confirm thrombocytopenia as an independent prognostic factor for disease progression and shortened survival in all disease subtypes except SM-AHNMD, where changes of blood cell counts mainly reflect the associated hematological neoplasm.…”

Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future

“…The prognosis in SSM regarding progression-free and overall survival is better than that in ASM or MCL, but is still poor when compared to typical ISM (excluding SSM). It is noteworthy that each B-Finding (criteria of SSM) by itself, including organomegaly, high tryptase level (>200 ng/ml), and evidence of clonal involvement of non-MC lineages, indicates a poor prognosis (35,42–46). …”

“…volumetric techniques) may be helpful to quantify organomegaly (45). It has also been described that multi-color flow cytometry and cell sorting improves evaluation of lineage involvement in SM (25,46,66) and that multi-lineage involvement in ISM/SSM is of prognostic significance (35,46,66). Moreover, it has been described that a certain KIT D816V allele burden in the PB (5–10%) reflects multi-lineage involvement (30,46).…”

Analysis of the function of microRNA-375 in humans using bioinformatics

“…The KIT protein is a type 3 transmembrane receptor of mast cell growth factor. The gene mutations were reported to be associated with gastrointestinal stromal tumors, acute myeloid leukemia, peel spot disease and large cell disease (25). The AGT protein participates in the pathogenesis and progression of hypertension and pre-eclampsia.…”

“…The functions of the above-mentioned hub proteins indicate that the hub proteins were particularly important in certain BPs, and primarily regulated the development and progression of cancer, hypertension, essential thrombocythemia and inflammation. Recent studies reveal that certain hub proteins may serve as novel biomarkers and targets in certain diseases (20,23,25,27,28).…”