TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 03/2009; 23(5):905-11. DOI: 10.1038/leu.2009.47
Source: PubMed


High-throughput DNA sequence analysis was used to screen for TET2 mutations in bone marrow-derived DNA from 239 patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). Thirty-two mutations (19 frameshift, 10 nonsense, 3 missense; mostly involving exons 4 and 12) were identified for an overall mutational frequency of approximately 13%. Specific diagnoses included polycythemia vera (PV; n=89), essential thrombocythemia (ET; n=57), primary myelofibrosis (PMF; n=60), post-PV MF (n=14), post-ET MF (n=7) and blast phase PV/ET/MF (n=12); the corresponding mutational frequencies were approximately 16, 5, 17, 14, 14 and 17% (P=0.50). Mutant TET2 was detected in approximately 17 and approximately 7% of JAK2V617F-positive and -negative cases, respectively (P=0.04). However, this apparent clustering of the two mutations was accounted for by an independent association between mutant TET2 and advanced age; mutational frequency was approximately 23% in patients > or =60 years old versus approximately 4% in younger patients (P<0.0001). The presence of mutant TET2 did not affect survival, leukemic transformation or thrombosis in either PV or PMF; a correlation with hemoglobin <10 g per 100 ml in PMF was noted (P=0.05). We conclude that TET2 mutations occur in both JAK2V617F-positive and -negative MPN, are more prevalent in older patients, display similar frequencies across MPN subcategories and disease stages, and hold limited prognostic relevance.


Available from: Terra Lasho, Aug 07, 2014
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    • "TET2 is an enzyme that catalyzes the conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and further modified cytosines, regulating gene expression at the cellular level [14], [15]. Loss-of-function mutations in TET2 have been reported in a variety of hematological malignancies including acute myeloid leukemias (AMLs), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDS) and lymphoid malignancies [16], [17], [18]. In mouse models, loss of one or both copies of Tet2 has been shown to contribute to the pathogenesis of hematological malignancies by increasing the self-renewal capacity of the hematopoietic stem cell compartment and expanding the immature pool of myeloid and lymphoid progenitors [19], [20], [21]. "
    [Show abstract] [Hide abstract] ABSTRACT: Systemic Mastocytosis (SM) is a clonal disease characterized by abnormal accumulation of mast cells in multiple organs. Clinical presentations of the disease vary widely from indolent to aggressive forms, and to the exceedingly rare mast cell leukemia. Current treatment of aggressive SM and mast cell leukemia is unsatisfactory. An imatinib-resistant activating mutation of the receptor tyrosine kinase KIT (KIT D816V) is most frequently present in transformed mast cells and is associated with all clinical forms of the disease. Thus the etiology of the variable clinical aggressiveness of abnormal mast cells in SM is unclear. TET2 appears to be mutated in primary human samples in aggressive types of SM, suggesting a possible role in disease modification. In this report, we demonstrate the cooperation between KIT D816V and loss of function of TET2 in mast cell transformation and demonstrate a more aggressive phenotype in a murine model of SM when both mutations are present in progenitor cells. We exploit these findings to validate a combination treatment strategy targeting the epigenetic deregulation caused by loss of TET2 and the constitutively active KIT receptor for the treatment of patients with aggressive SM.
    Full-text · Article · May 2014 · PLoS ONE
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    • "The relationship between TET2 mutations and prognosis is unclear and different studies have shown conflicting results. It is likely that TET2 mutations do not affect MPN prognosis but may be a marker of better prognosis in MDS patients [53, 56]. Prognostic implications in AML are uncertain. "
    [Show abstract] [Hide abstract] ABSTRACT: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Certain cytogenetic and molecular genetic mutations are recognized to have an impact on prognosis, leading to their inclusion in some prognostic stratification systems. Recently, the advent of high-throughput whole genome or exome sequencing has led to the identification of several novel recurrent mutations in AML, a number of which have been found to involve genes concerned with epigenetic regulation. These genes include in particular DNMT3A, TET2, and IDH1/2, involved with regulation of DNA methylation, and EZH2 and ASXL-1, which are implicated in regulation of histones. However, the precise mechanisms linking these genes to AML pathogenesis have yet to be fully elucidated as has their respective prognostic relevance. As massively parallel DNA sequencing becomes increasingly accessible for patients, there is a need for clarification of the clinical implications of these mutations. This review examines the literature surrounding the biology of these epigenetic modifying genes with regard to leukemogenesis and their clinical and prognostic relevance in AML when mutated.
    Full-text · Article · Mar 2014 · Advances in Hematology
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    • "The stable TET2 mutational status from ET to overt AML indicates that loss of TET2 function was not implicated in disease progression in this case but rather represents an early priming event in the hematopoietic progenitors. Presence of multiple TET2 mutations, two loss-of-function and one missense variant, has not been described previously in ET patients [4]. The A1505T might be a rare normal germline variant, but involved tissue was not available for confirmation of this. "
    [Show abstract] [Hide abstract] ABSTRACT: Chronic myeloid neoplasms have susceptibility to transform into acute myeloid leukemia due to attainment of additional molecular lesions. We here describe the kinetics of a del(7q) driven leukemogenesis in a patient with multiple TET2 mutations and JAK2 V617F mutated chronic myeloproliferative neoplasm. The del(7q) emerged in the accelerated phase of disease, which was preceded by a lag phase of almost three years with normalized peripheral blood cell counts. Our results reveal that the del(7q), independently of other lesions, acts as a leukemic driver in this patient and that the stable long-lasting normalization of peripheral blood cell values concealed pending transformation.
    Full-text · Article · Dec 2013 · Leukemia Research Reports
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