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

Abstract

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 ~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 ~16, 5, 17, 14, 14 and 17% (P=0.50). Mutant TET2 was detected in ~17 and ~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 ~23% in patients ≥60 years old versus ~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.

TET2 mutations in childhood leukemia

“…Mutations and deletions were detected in myelodysplastic syndromes, acute myeloid leukemias (AML) and other myeloid malignancies. [1][2][3][4][5] So far, however, the presence of TET2 mutations has not been reported in childhood leukemia.…”

Mutations du gèneTET2dans les hémopathies myéloïdes humaines

“…Une fréquence élevée de mutations de TET2 a maintenant été rapportée dans diverses pathologies malignes myéloï-des humaines [8][9][10][11][12][13][14]. La caractérisa-tion d'un événement oncogénique commun à plusieurs hémopathies myéloïdes pourrait permettre une réévaluation de leur classification.…”

Molecular basis and clonal evolution of myeloproliferative neoplasms

“…TET2 deficient mice often present with reduced levels of methylated cytosines in their genome alongside defects in the hematopoietic department [47][48][49]. Both muta tions and deletions of the TET2 gene have been frequently observed in patients, with mutations occurring in 13% and deletions in approximately 3% [27,44,45]. A recent finding has shed more light on the function of TET2, where somatic mutations were found in normal elderly individuals pre senting with clonal hematopoiesis [50].…”

“…TET2 encodes an enzyme that catalyses the switch of 5 methyl cytosine into hydroxymethylated cytosine, requiring Fe(II) and α ketoglurate [43]. The sequencing of patient samples has revealed many mutations targeting the TET2 gene, indicating a possible role of the protein in disease development [44][45][46]. It is speculated that TET2 affects gene expression through its role in DNA demethyla tion.…”