Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates

Abstract

TET2 (TET oncogene family member 2) is a candidate tumor suppressor gene located at chromosome 4q24, and was recently reported to be mutated in ~14% of patients with JAK2 V617F-positive myeloproliferative neoplasms. We used high-throughput DNA sequence analysis to screen for TET2 mutations in bone marrow-derived DNA from 48 patients with systemic mastocytosis (SM), including 42 who met the 2008 WHO (World Health Organization) diagnostic criteria for SM and 6 with FIP1L1-PDGFRA. Twelve (29%) SM, but no FIP1L1-PDGFRA patients, had TET2 mutations. A total of 17 mutations (13 frameshift, 2 nonsense and 2 missense) were documented in 2 (15%) of 13 indolent SM patients, 2 (40%) of 5 aggressive SM, and 8 (35%) of 23 SM associated with a clonal non-mast cell-lineage hematopoietic disease (P = 0.52). KITD816V was detected by PCR sequencing in 50 or 20% of patients with or without TET2 mutation (P = 0.05), respectively. Multivariable analysis showed a significant association between the presence of TET2 mutation and monocytosis (P = 0.0003) or female sex (P = 0.05). The association with monocytosis was also observed in non-indolent SM (n = 29), in which the presence of mutant TET2 did not affect survival (P = 0.98). We conclude that TET2 mutations are frequent in SM, segregate with KIT D816V and influence phenotype without necessarily altering prognosis.

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.…”

One Thousand Patients With Primary Myelofibrosis: The Mayo Clinic Experience

“…MPL and JAK2 mutation analyses were performed according to previously published methods. [26][27][28][29] IDH1 and IDH2 mutations were analyzed by direct sequencing and/or high-resolution melting assay. 30 Unfavorable karyotype designation 31 and International Prognostic Scoring System (IPSS), 32 DIPSS, 33 and DIPSSplus 21 21 Leukemic transformation risk was considered high in the presence of unfavorable karyotype or platelet count less than 100 ϫ 10 9 /L or low in the absence of both of these risk factors.…”

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.…”