2009.06.08 – Mutation in TET2 in Myeloid Cancers

http://www.citeulike.org/user/absterga/article/4772094?citation_format=achemso#

 

Mutation in TET2 in Myeloid Cancers

by: Francois Delhommeau, Sabrina Dupont, Veronique D Valle, Chloe James, Severine Trannoy, Aline Masse, Olivier Kosmider, Jean-Pierre Le Couedic, Fabienne Robert, Antonio Alberdi, Yann Lecluse, Isabelle Plo, Francois J Dreyfus, Christophe Marzac, Nicole Casadevall, Catherine Lacombe, Serge P Romana, Philippe Dessen, Jean Soulier, Franck Viguie, Michaela Fontenay, William Vainchenker, Olivier A Bernard

Delhommeau, F. et al. N Engl J Med 2009, 360, 2289-2301.

 

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N Engl J Med. 2009 May 28;360(22):2355-7.

 

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 Abstract

Background The myelodysplastic syndromes and myeloproliferative disorders are associated with deregulated production of myeloid cells. The mechanisms underlying these disorders are not well defined. Methods We conducted a combination of molecular, cytogenetic, comparative-genomic-hybridization, and single-nucleotide-polymorphism analyses to identify a candidate tumor-suppressor gene common to patients with myelodysplastic syndromes, myeloproliferative disorders, and acute myeloid leukemia (AML). The coding sequence of this gene, TET2, was determined in 320 patients. We analyzed the consequences of deletions or mutations in TET2 with the use of in vitro clonal assays and transplantation of human tumor cells into mice. Results We initially identified deletions or mutations in TET2 in three patients with myelodysplastic syndromes, in three of five patients with myeloproliferative disorders, in two patients with primary AML, and in one patient with secondary AML. We selected the six patients with myelodysplastic syndromes or AML because they carried acquired rearrangements on chromosome 4q24; we selected the five patients with myeloproliferative disorders because they carried a dominant clone in hematopoietic progenitor cells that was positive for the V617F mutation in the Janus kinase 2 (JAK2) gene. TET2 defects were observed in 15 of 81 patients with myelodysplastic syndromes (19%), in 24 of 198 patients with myeloproliferative disorders (12%) (with or without the JAK2 V617F mutation), in 5 of 21 patients with secondary AML (24%), and in 2 of 9 patients with chronic myelomonocytic leukemia (22%). TET2 defects were present in hematopoietic stem cells and preceded the JAK2 V617F mutation in the five samples from patients with myeloproliferative disorders that we analyzed. Conclusions Somatic mutations in TET2 occur in about 15% of patients with various myeloid cancers. 10.1056/NEJMoa0810069

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