2009.09.10 -Mutation in TET2 in Myeloid Cancers

http://content.nejm.org/cgi/content/full/361/11/1117

The New England Journal of Medicine

Volume 361:1117-1118 September 10, 2009 Number 11

[Full Text:

http://content.nejm.org/cgi/content/full/360/22/2289?ijkey=6b63c1c1522245709489edf9f696d13377f74db7 ]

http://debashishbanerji.com/creativewriting/anima/ Mutation in TET2 in Myeloid Cancers

To the Editor: The finding of Delhommeau and colleagues that TET2 mutations occur in myeloid cancers (May 28 issue)1 has been confirmed by others.2,3,4,5 The presence of single-copy and double-copy TET2 defects and the frequent occurrence of frameshift, nonsense, or deletion mutations are consistent with the notion that TET2 is a tumor suppressor. Delhommeau et al. suggest a role for TET2 in disease progression. We looked into this possibility by studying stored, serial bone marrow samples from eight patients with myeloproliferative neoplasms. Mutant TET2 was not detected in any of the follow-up samples, even though leukemic or fibrotic transformation occurred in three of these patients. These results are consistent with observations of similar frequencies of TET2 mutations in chronic and advanced-phase myeloproliferative neoplasms.3 We therefore believe that it is difficult to assign a specific role in the pathogenesis or progression of myeloproliferative neoplasms to mutant TET2.

Ayalew Tefferi, M.D.
Ken-Hong Lim, M.D.
Mayo Clinic
Rochester, MN
tefferi.ayalew@mayo.edu

Ross Levine, M.D.
Memorial Sloan-Kettering Cancer Center
New York, NY

http://bridgewaterfire.com/author/vada/ References

  1. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009;360:2289-2301.
  2. 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.
  3. 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.
  4. 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.
  5. 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.

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The authors reply: Recent reports support the designation of TET2 as a tumor-suppressor gene, which probably also acts through haploinsufficiency. The detection of sequence variation in TET2 is the only method of showing its inactivation. However, the absence of a mutation cannot preclude abnormal function of either copy of TET2. The inactivation of tumor-suppressor genes may contribute to the initiation and progression of the transformation process. Our data strongly support the occurrence of TET2 mutations in the initial steps of myeloid diseases but do not exclude the possibility that such mutations can occur later in the course of these diseases. The sequence of events can differ within a single disease entity or even within the same patient.1 It has been shown that mutation of the second copy of TET2 may occur later in the course of the disease, preceding progression.2,3 We agree that the unambiguous assignment of a specific role for TET2 mutations in the development of myeloid neoplasms is difficult and needs to be supported by experimental data.

Olivier A. Bernard, Ph.D.
INSERM E0210
Paris, France
olivier.bernard@inserm.fr

William Vainchenker, M.D., Ph.D.
Institut Gustave Roussy
Villejuif, France

References

  1. 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.
  2. Langemeijer SM, Kuiper RP, Berends M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 2009;41:838-842.
  3. 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).