BMSEHA15
Published online 1 October 2009
Haematologica, Vol 94, Issue 12, 1676-1681 doi:10.3324/haematol.2009.011205
Copyright © 2009 by Ferrata Storti Foundation
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Myelodysplastic/Myeloproliferative Neoplasms

TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia

Olivier Kosmider1,2,3,4, Véronique Gelsi-Boyer5, Marion Ciudad6,7, Cindy Racoeur6,7,8, Valérie Jooste6,7, Norbert Vey5, Bruno Quesnel9, Pierre Fenaux10,11, Jean-Noël Bastie6,7,8, Odile Beyne-Rauzy12, Aspasia Stamatoulas13, François Dreyfus1,2,3,4, Norbert Ifrah14, Stéphane de Botton15, William Vainchenker15, Oliver A. Bernard16, Daniel Birnbaum5, Michaëla Fontenay1,2,3,4, Eric Solary6,7,8,15 on behalf of the Groupe Francophone des Myélodysplasies

1 Hematology Department, Hôpital Cochin (APHP), Paris
2 Inserm U567, Paris
3 CNRS UMR 8104, Paris
4 University Paris 5, Faculty of Medicine René Descartes, UM 3, Paris
5 Hematology Department, Institut Paoli-Calmettes, Marseille
6 Inserm UMR866, 7 Boulevard Jeanne d’Arc, Dijon
7 University of Burgundy, Faculty of Medicine, 7 Boulevard Jeanne d’Arc, Dijon
8 CHU Le Bocage, Dijon
9 CHU Lille, Lille
10 Hôpital Avicenne (APHP)/ University Paris 13, Bobigny
11 Inserm U848, Institut Gustave Roussy/University Paris 11, Villejuif
12 CHU Purpan, Toulouse
13 CHU Rouen, Rouen
14 CHU Angers, Angers
15 Inserm U790, Institut Gustave Roussy/University Paris 11, Villejuif
16 Inserm E010, Hôpital Necker/University Paris 5, Paris, France

Correspondence: Eric Solary, Inserm UMR866, Faculty of Medicine, 7 boulevard Jeanne d’Arc, 21000 Dijon, France. E-mail: esolary{at}u-bourgogne.fr

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.

Design and 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.

Key words: TET2 gene, mutation, chronic myelomonocytic leukemia.