2009.07.02 – Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies


Blood, 2 July 2009, Vol. 114, No. 1, pp. 144-147.

Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies
Omar Abdel-Wahab1,2, Ann Mullally3,4, Cyrus Hedvat5, Guillermo Garcia-Manero6, Jay Patel1, Martha Wadleigh3, Sebastien Malinge7, JinJuan Yao5, Outi Kilpivaara1, Rukhmi Bhat7, Kety Huberman1, Sabrena Thomas1, Igor Dolgalev1, Adriana Heguy1, Elisabeth Paietta8, Michelle M. Le Beau9, Miloslav Beran6, Martin S. Tallman7, Benjamin L. Ebert4,10,11, Hagop M. Kantarjian6, Richard M. Stone3, D. Gary Gilliland4,1012, John D. Crispino7, and Ross L. Levine1,2
1 Human Oncology and Pathogenesis Program, and 2 Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 4 Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA; 5 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; 6 Department of Leukemia, M. D. Anderson Cancer Center, Houston, TX; 7 Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL; 8 Montefiore Medical Center–North Division, New York Medical College, New York; 9 Section of Hematology/Oncology, University of Chicago, IL; 10 Harvard Stem Cell Institute, Boston, MA; 11 Broad Institute of Harvard and Massachusetts Institute of Technology, Boston; and 12 Howard Hughes Medical Institute, Harvard Medical School, Boston, MA

Disease alleles that activate signal transduction are common in myeloid malignancies; however, there are additional unidentified mutations that contribute to myeloid transformation. Based on the recent identification of TET2 mutations, we evaluated the mutational status of TET1, TET2, and TET3 in myeloproliferative neoplasms (MPNs), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). Sequencing of TET2 in 408 paired tumor/normal samples distinguished between 68 somatic mutations and 6 novel single nucleotide polymorphisms and identified TET2 mutations in MPN (27 of 354, 7.6%), CMML (29 of 69, 42%), AML (11 of 91, 12%), and M7 AML (1 of 28, 3.6%) samples. We did not identify somatic TET1 or TET3 mutations or TET2 promoter hypermethylation in MPNs. TET2 mutations did not cluster in genetically defined MPN, CMML, or AML subsets but were associated with decreased overall survival in AML (P = .029). These data indicate that TET2 mutations are observed in different myeloid malignancies and may be important in AML prognosis.