Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis

Abstract

Cooperating genetic events are likely to contribute to the phenotypic diversity of KIT-D816V systemic mastocytosis. In this study, 44 patients with KIT-D816V systemic mastocytosis were evaluated for coexisting NRAS, KRAS, HRAS or MRAS mutations. Activating NRAS mutations were identified in 2 of 8 patients with advanced disease. NRAS mutations were not found in patients with indolent systemic mastocytosis. To better understand the clonal evolution of mastocytosis, we evaluated the cell compartments impacted by the NRAS and KIT mutations. Clonal mast cells harbored both mutations. KIT-D816V was not detected in bone marrow CD34 + progenitors, whereas the NRAS mutation was present. These findings suggest that NRAS mutations may have the potential to precede KIT-D816V in clonal development. Unlike other mature lineages, mast cell survival is dependent on KIT and the presence of these two activating mutations may have a greater impact on the expansion of this cell compartment and in resultant disease severity. (Clinicaltrials.gov identifier: NCT00044122, NCT00001756)

Chronic mast cell leukemia: A novel leukemia-variant with distinct morphological and clinical features

“…Europe PMC Funders Author Manuscripts leukemic expansion of MCs in these patients which is consistent with recent studies [39][40][41]. However, whereas in chronic MCL a few additional lesions may be sufficient, many more lesions may be required to cause acute MCL.…”

SRSF2-p95 hotspot mutation is highly associated with advanced forms of mastocytosis and mutations in epigenetic regulator genes

“…Efforts to discriminate and to predict the clinical course of mastocytosis have uncovered genetic mutations that figure prominently in this disease. KITD816V mutation is the most common (>80% of mastocytosis cases) and is thought to drive the expansion of affected clones towards the mast cell lineage, 6 but does not segregate with advanced disease. In contrast, TET2 mutation, found in approximately 20% of patients, is associated with aggressive forms of mastocytosis.…”

Diagnosis and management of mastocytosis: an emerging challenge in applied hematology

“…These lesions include, among others, mutations in TET2, SRSF2, ASXL1, CBL, RUNX1, and RAS (Table 4). [29][30][31][32] Such additional lesions may be coexpressed with KIT D816V in the same cells (same subclones) but may also be detectable in other myeloid lineages, especially in patients with SM-AHNMD. Based on colony assays, KIT D816V appears to be a late event in such patients.…”

“…Moreover, several other drug targets have been identified recently in patients with SM-AHNMD. [30][31][32] Therefore, it is of utmost importance to apply the full armamentarium of molecular markers in these patients.…”