Correspondence
Mutation in TET2 in Myeloid Cancers
N Engl J Med 2009; 361:1117-1118September 10, 2009
- Article
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.2-5 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.
5 ReferencesAyalew 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, NY1
Delhommeau F ,Dupont S ,Della Valle V , et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009;360:2289-2301
Full Text | Web of Science | Medline2
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 | Medline3
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 | Medline4
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 | Medline5
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
CrossRef | Web of Science | Medline
Author/Editor Response
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.
3 ReferencesOlivier A. Bernard, Ph.D.
INSERM E0210, Paris, France
olivier.bernard@inserm. fr William Vainchenker, M.D., Ph.D.
Institut Gustave Roussy, Villejuif, France1
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
CrossRef | Web of Science | Medline2
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 | Medline3
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).
- Citing Articles (6)
Citing Articles
1
Olaya Villa, Mar Mallo, Nadezda Kosyakova, Marta Salido, Thomas Liehr, Luz Martínez-Avilés, Carmen Pedro, Manel García-Aragonés, Blanca Espinet, Beatriz Bellosillo, Lourdes Florensa, Leonor Arenillas, Ivon Cuscó, Luis A. Pérez Jurado, Francesc Solé. (2011) Deletion of TET2 gene in an acute myeloid leukemia case with a t(4;15)(q24;q26) characterized by glass needle based chromosome microdissection and oligonucleotide array. Leukemia Research 35:9, e161-e163
CrossRef2
John Mascarenhas, Nitin Roper, Pratima Chaurasia, Ronald Hoffman. (2011) Epigenetic abnormalities in myeloproliferative neoplasms: a target for novel therapeutic strategies. Clinical Epigenetics 2:2, 197-212
CrossRef3
Olfat Ismael, Akira Shimada, Asahito Hama, Hiroshi Sakaguchi, Sayoko Doisaki, Hideki Muramatsu, Nao Yoshida, Masafumi Ito, Yoshiyuki Takahashi, Naohiro Akita, Shosuke Sunami, Yoshitoshi Ohtsuka, Youji Asada, Hiroyuki Fujisaki, Seiji Kojima. (2011) Mutations profile of polycythemia vera and essential thrombocythemia among Japanese children. Pediatric Blood & Cancern/a-n/a
CrossRef4
Benoîte Pérez, Olivier Kosmider, Bruno Cassinat, Aline Renneville, Julie Lachenaud, Sophie Kaltenbach, Yves Bertrand, André Baruchel, Christine Chomienne, Michaela Fontenay, Claude Preudhomme, Hélène Cavé. (2010) Genetic typing of CBL, ASXL1, RUNX1, TET2 and JAK2 in juvenile myelomonocytic leukaemia reveals a genetic profile distinct from chronic myelomonocytic leukaemia. British Journal of Haematology 151:5, 460-468
CrossRef5
A Tefferi. (2010) Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 24:6, 1128-1138
CrossRef6
Ayalew Tefferi. (2010) Mutational analysis in BCR-ABL -negative classic myeloproliferative neoplasms: impact on prognosis and therapeutic choices. Leukemia & Lymphoma 51:4, 576-582
CrossRef
