Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies.
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.
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Omar
O
Abdel-Wahab
Ann
A
Mullally
Cyrus
C
Hedvat
Guillermo
G
Garcia-Manero
Jay
J
Patel
Martha
M
Wadleigh
Sebastien
S
Malinge
JinJuan
J
Yao
Outi
O
Kilpivaara
Rukhmi
R
Bhat
Kety
K
Huberman
Sabrena
S
Thomas
Igor
I
Dolgalev
Adriana
A
Heguy
Elisabeth
E
Paietta
Michelle M
MM
Le Beau
Miloslav
M
Beran
Martin S
MS
Tallman
Benjamin L
BL
Ebert
Hagop M
HM
Kantarjian
Richard M
RM
Stone
D Gary
DG
Gilliland
John D
JD
Crispino
Ross L
RL
Levine
D016022:Case-Control Studies; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D005091:Exons; D016368:Frameshift Mutation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics*; D006899:Mixed Function Oxygenases; D009154:Mutation; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017384:Sequence Deletion; D015996:Survival Rate
D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human