Mastocytosis: a mutated KIT receptor induced myeloproliferative disorder

Abstract

Although more than 90% systemic mastocytosis (SM) patients express gain of function mutations in the KIT receptor, recent next generation sequencing has revealed the presence of several additional genetic and epigenetic mutations in a subset of these patients, which confer poor prognosis and inferior overall survival. A clear understanding of how genetic and epigenetic mutations cooperate in regulating the tremendous heterogeneity observed in these patients will be essential for designing effective treatment strategies for this complex disease. In this review, we describe the clinical heterogeneity observed in patients with mastocytosis, the nature of relatively novel mutations identified in these patients, therapeutic strategies to target molecules downstream from activating KIT receptor and finally we speculate on potential novel strategies to interfere with the function of not only the oncogenic KIT receptor but also epigenetic mutations seen in these patients.

En mann i 70-årene med ryggsmerter, mageplager og utslett

“…Mastocytose tenkes å ha sitt opphav fra muterte hematopoetiske stamceller (12). Studier har vist at > 90 % av pasientene har en aktiverende mutasjon i genet KIT, der over 80 % av disse vil ha en bestemt punktmutasjon i ekson 17, KITD816 V (13,14). KIT er en transmembran tyrosinkinasereseptor for stamcellefaktor CD117 (6,13).…”

“…To uker etter at pasienten kom hjem fra sykehuset, viste blodprøver tatt hos fastlegen nytilkommet anemi med hemoglobin 11,5 g/dl (13,(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Automatisk differensialtelling tatt ved fastlegekontoret anga «blastalarm», og det ble utført supplerende blodutstryk som ble vurdert av hematolog ved lokalsykehuset.…”

Molecular Genetic Abnormalities in the Pathogenesis of Hematologic Malignancies and Corresponding Changes in Cell Signaling Systems

“…Гепатолиенальная Т-клеточная лимфома 7q i (7) [6,115,116] Системный мастоцитоз (+/-поражение кожи) Системный мастоцитоз, сочетающийся с гематологическими нарушениями (+/-поражение кожи) Тучноклеточный лейкоз/саркома даст возможность разработать новые молекулы для доклинических и клинических исследований и/или перепрофилировать уже известные препараты, что может привести к оптимизации терапевтической тактики и улучшению показателей выживаемости пациентов.…”

A variant c-KITmutation, D816H, fundamental to the sequential development of an ovarian mixed germ cell tumor and systemic mastocytosis with chronic myelomonocytic leukemia

“…In the light of increased, atypical mast cells on bone marrow evaluation, elevated tryptase (158 μg/l), and clinical symptoms including flushing, tachycardia, and hypotension, evaluation for systemic mastocytosis was undertaken. Molecular study for the KIT D816V mutation was negative, but next‐generation sequencing identified a KIT D816H in the peripheral blood, fulfilling diagnostic criteria for systemic mastocytosis with associated hematological nonmast cell disease, specifically SM‐CMML . Next‐generation sequencing was also performed on the GCT and identified the identical KIT mutation in both the teratoma and the dysgerminoma components; the yolk sac tumor was not evaluated.…”