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.

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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]. "
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    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.
    PLoS ONE 05/2014; 9(5):e96209. DOI:10.1371/journal.pone.0096209 · 3.23 Impact Factor
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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. "
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    Advances in Hematology 03/2014; 2014(8):103175. DOI:10.1155/2014/103175
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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. "
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