TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia.
BACKGROUND
Acquired somatic deletions and loss-of-function mutations in one or several codons of the TET2 (Ten-Eleven Translocation-2) gene were recently identified in hematopoietic cells from patients with myeloid malignancies, including myeloproliferative disorders and myelodys-plastic syndromes. The present study was designed to determine the prevalence of TET2 gene alterations in chronic myelomonocytic leukemias.


METHODS
Blood and bone marrow cells were collected from 88 patients with chronic phase chronic myelomonocytic leukemia and from 14 with acute transformation of a previously identified disease. Polymerase chain reaction analysis and direct sequencing were used to sequence exons 3 to 11 of the TET2 gene. Annotated single nucleotide polymorphisms were excluded. Survival curves were constructed by the Kaplan-Meier method.


RESULTS
We detected TET2 mutations in 44 of 88 (50%) patients with chronic myelomonocytic leukemia, which suggests that TET2 gene mutations are especially frequent in this myeloid disease. A TET2 gene alteration was identified in 18 of the 43 patients studied at diagnosis and was associated with a trend to a lower overall survival rate; confining the analysis to the 29 patients with chronic myelomonocytic leukemia-1, according to the WHO classification, the difference in overall survival between patients with or without TET2 gene mutations became statistically significant.


CONCLUSIONS
TET2 gene alterations are more frequent in chronic myelomonocytic leukemia than in other subgroups of hematopoietic diseases studied so far and could negatively affect the patients' outcome. The striking association between TET2 gene alterations and monocytosis, already observed in patients with systemic mastocytosis, could indicate a negative role of TET2 in the control of monocytic lineage determination.
Kosmider
Olivier
O
Hematology Department, Hôpital Cochin (APHP), Paris, France.
Gelsi-Boyer
Véronique
V
Ciudad
Marion
M
Racoeur
Cindy
C
Jooste
Valérie
V
Vey
Norbert
N
Quesnel
Bruno
B
Fenaux
Pierre
P
Bastie
Jean-Noël
JN
Beyne-Rauzy
Odile
O
Stamatoulas
Aspasia
A
Dreyfus
François
F
Ifrah
Norbert
N
de Botton
Stéphane
S
Vainchenker
William
W
Bernard
Oliver A
OA
Birnbaum
Daniel
D
Fontenay
Michaëla
M
Solary
Eric
E
D000368:Aged; D000369:Aged, 80 and over; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis / Q000706:statistics & numerical data; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D005260:Female; D005787:Gene Frequency; D006801:Humans; D053208:Kaplan-Meier Estimate; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human