To the Editor: The finding of Delhommeau and colleagues thatTET2 mutations occur in myeloid cancers (May 28 issue)1 hasbeen confirmed by others.2,3,4,5 The presence of single-copyand double-copy TET2 defects and the frequent occurrence offrameshift, nonsense, or deletion mutations are consistent withthe notion that TET2 is a tumor suppressor. Delhommeau et al.suggest a role for TET2 in disease progression. We looked intothis possibility by studying stored, serial bone marrow samplesfrom eight patients with myeloproliferative neoplasms. MutantTET2 was not detected in any of the follow-up samples, eventhough leukemic or fibrotic transformation occurred in threeof these patients. These results are consistent with observationsof similar frequencies of TET2 mutations in chronic and advanced-phasemyeloproliferative neoplasms.3 We therefore believe that itis difficult to assign a specific role in the pathogenesis orprogression of myeloproliferative neoplasms to mutant TET2.
Ross Levine, M.D. Memorial Sloan-Kettering Cancer Center New York, NY
References
Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009;360:2289-2301. [Free Full Text]
Tefferi A, Levine RL, Lim KH, et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia 2009;23:900-904. [CrossRef][Web of Science][Medline]
Tefferi A, Pardanani A, Lim KH, et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia 2009;23:905-911. [CrossRef][Web of Science][Medline]
Tefferi A, Lim KH, Abdel-Wahab O, et al. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. Leukemia 2009;23:1343-1345. [CrossRef][Web of Science][Medline]
Abdel-Wahab O, Mullally A, Hedvat C, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009;114:144-147. [Free Full Text]
The authors reply: Recent reports support the designation ofTET2 as a tumor-suppressor gene, which probably also acts throughhaploinsufficiency. The detection of sequence variation in TET2is the only method of showing its inactivation. However, theabsence of a mutation cannot preclude abnormal function of eithercopy of TET2. The inactivation of tumor-suppressor genes maycontribute to the initiation and progression of the transformationprocess. Our data strongly support the occurrence of TET2 mutationsin the initial steps of myeloid diseases but do not excludethe possibility that such mutations can occur later in the courseof these diseases. The sequence of events can differ withina single disease entity or even within the same patient.1 Ithas been shown that mutation of the second copy of TET2 mayoccur later in the course of the disease, preceding progression.2,3 We agree that the unambiguous assignment of a specific rolefor TET2 mutations in the development of myeloid neoplasms isdifficult and needs to be supported by experimental data.
Olivier A. Bernard, Ph.D. INSERM E0210 Paris, France olivier.bernard{at}inserm.fr
William Vainchenker, M.D., Ph.D. Institut Gustave Roussy Villejuif, France
References
Li S, Kralovics R, De Libero G, Theocharides A, Gisslinger H, Skoda RC. Clonal heterogeneity in polycythemia vera patients with JAK2 exon12 and JAK2-V617F mutations. Blood 2008;111:3863-3866. [Free Full Text]
Langemeijer SM, Kuiper RP, Berends M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 2009;41:838-842. [CrossRef][Web of Science][Medline]
Saint-Martin C, Leroy G, Delhommeau F, et al. Analysis of the ten-eleven translocation (TET)2 gene in familial myeloproliferative neoplasms. Blood 2009 June 29 (Epub ahead of print).
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