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

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 similar to 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 similar to 16, 5, 17, 14, 14 and 17% (P = 0.50). Mutant TET2 was detected in similar to 17 and similar to 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 similar to 23% in patients >= 60 years old versus similar to 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. Leukemia (2009) 23, 905-911; doi: 10.1038/leu.2009.47;published online 5 March 2009