Single Nucleotide Polymorphism Array Lesions, TET2, DNMT3A, ASXL1 and CBL Mutations Are Present in Systemic Mastocytosis

Abstract

We hypothesized that analysis of single nucleotide polymorphism arrays (SNP-A) and new molecular defects may provide new insight in the pathogenesis of systemic mastocytosis (SM). SNP-A karyotyping was applied to identify recurrent areas of loss of heterozygosity and bidirectional sequencing was performed to evaluate the mutational status of TET2, DNMT3A, ASXL1, EZH2, IDH1/IDH2 and the CBL gene family. Overall survival (OS) was analyzed using the Kaplan-Meier method. We studied a total of 26 patients with SM. In 67% of SM patients, SNP-A karyotyping showed new chromosomal abnormalities including uniparental disomy of 4q and 2p spanning TET2/KIT and DNMT3A. Mutations in TET2, DNMT3A, ASXL1 and CBL were found in 23%, 12%, 12%, and 4% of SM patients, respectively. No mutations were observed in EZH2 and IDH1/IDH2. Significant differences in OS were observed for SM mutated patients grouped based on the presence of combined TET2/DNMT3A/ASXL1 mutations independent of KIT (P = 0.04) and sole TET2 mutations (P<0.001). In conclusion, TET2, DNMT3A and ASXL1 mutations are also present in mastocytosis and these mutations may affect prognosis, as demonstrated by worse OS in mutated patients.

Dnmt3a restrains mast cell inflammatory responses

“…1B). This is in accordance with the fact that DNMT3A is frequently mutated in myeloid neoplasms, including systemic mastocytosis (14), and deletion of this enzyme predisposes the cells to myeloid transformation (18). To assess whether such increased proliferation was also associated with increased survival in vitro, mast cells were transiently deprived of the essential survival factor IL-3.…”

“…Importantly, aberrant DNA methylation is a hallmark of many diseases, including autoimmune diseases and especially various types of cancer (4,5). Mutations in DNMT3A have been found in a variety of hematological malignancies (4,12,13), including systemic mastocytosis, a clonal proliferative disorder of mast cells (14), pointing toward a role for DNMT3A in modulating mast cell biology. Further correlating DNA methylation with the biology of mast cells (which are key effector cells in asthmatic and allergic responses), a recent survey compared atopic and asthmatic patients with healthy controls and identified 81 differentially methylated regions (15); the hypomethylated regions included genes such as IL13, which is not only crucial in asthma pathogenesis but is also expressed at high levels by mast cells (16).…”

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.…”

SF3B1 mutations are infrequently found in non-myelodysplastic bone marrow failure syndromes and mast cell diseases but, if present, are associated with the ring sideroblast phenotype

“…We recently reported that a pattern of mutations (c-KIT, TET2, IDH1/2, DNMT3A, EZH2, ASXL1, and CBL) is associated with SM. 13 Conversely these genes are usually found in CMML, a disease that sometimes co-exists with mastocytosis. Mutational analysis in the index cases showed a wild-type configuration for these genes.…”