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.
Abdel-Wahab
Omar
O
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Mullally
Ann
A
Hedvat
Cyrus
C
Garcia-Manero
Guillermo
G
Patel
Jay
J
Wadleigh
Martha
M
Malinge
Sebastien
S
Yao
JinJuan
J
Kilpivaara
Outi
O
Bhat
Rukhmi
R
Huberman
Kety
K
Thomas
Sabrena
S
Dolgalev
Igor
I
Heguy
Adriana
A
Paietta
Elisabeth
E
Le Beau
Michelle M
MM
Beran
Miloslav
M
Tallman
Martin S
MS
Ebert
Benjamin L
BL
Kantarjian
Hagop M
HM
Stone
Richard M
RM
Gilliland
D Gary
DG
Crispino
John D
JD
Levine
Ross L
RL
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