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.
Unlike the case with thrombosis, prognostic models for survival and leukemic transformation (LT) in essential thrombocythemia (ET) are not available. Among 605 patients with ET seen at our institution and followed for a median of 84 months, 155 died and LT was documented in 20 patients (3.3%). In a multivariable analysis, hemoglobin level below normal (females o120 g/l; males o135 g/l) was identified as an independent risk factor for both inferior survival and LT. Additional risk factors for survival included age X60 years, leukocyte count X15 Â 10 9 /l, smoking, diabetes mellitus and thrombosis. For LT, platelet count X1000 Â 10 9 /l but not cytoreductive therapy was flagged as an additional independent risk factor. In fact, four of the 20 patients (20%) with LT were untreated previously. We used the above information to construct prognostic models that effectively discriminated among low-, intermediate-and high-risk groups with respective median survivals of 278, 200 and 111 months (Po0.0001), and LT rates of 0.4, 4.8 and 6.5% (P ¼ 0.0009) respectively. Presence of JAK2V617F did not impact either survival or LT and mutational frequency was similar among the different risk groups.
Thanatos-associated proteins (THAPs) are zinc-dependent, sequence-specific DNA-binding factors involved in cell proliferation, apoptosis, cell cycle, chromatin modification and transcriptional regulation. THAP11 is the most recently described member of this human protein family. In this study, we show that THAP11 is ubiquitously expressed in normal tissues and frequently downregulated in several human tumor tissues. Overexpression of THAP11 markedly inhibits growth of a number of different cells, including cancer cells and non-transformed cells. Silencing of THAP11 by RNA interference in HepG2 cells results in loss of cell growth repression. These results suggest that human THAP11 may be an endogenous physiologic regulator of cell proliferation. We also provide evidence that the function of THAP11 is mediated by its ability to repress transcription of c-Myc. Promoter reporter assays indicate a DNA binding-dependent c-Myc transcriptional repression. Chromatin immunoprecipitations and EMSA assay suggest that THAP11 directly binds to the c-Myc promoter. The findings that expression of c-Myc rescues significantly cells from THAP11-mediated cell growth suppression and that THAP11 expression only slightly inhibits c-Myc null fibroblasts cells growth reveal that THAP11 inhibits cell growth through downregulation of c-Myc expression. Taken together, these suggest that THAP11 functions as a cell growth suppressor by negatively regulating the expression of c-Myc. Cell Death and Differentiation (2009) 16, 395-405; doi:10.1038/cdd.2008 published online 14 November 2008 The THAP proteins (Thanatos-associated protein), a novel family of cellular factors, are characterized by the presence of an evolutionarily conserved protein motif. The motif designated as the THAP domain presents striking similarities with the site-specific DNA-binding domain of Drosophila P element transposase.
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