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

Abstract

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.

Figure 1.

Schematic representation of the location of the 68 mutations identified in 46 patients with CMLL patients, of whom 44 in chronic phase CMML and 2 in blastic transformation. Two distinct mutations were identified in 19 of these patients (see Table 2); 29 frameshifts (white triangles); 20 nonsense mutations (hatched triangles), 16 missense mutations (gray triangles) and 3 mutations in splice sites (black triangles) are indicated. Gray bars indicate conserved domains (AA 1134–1444 and 1842–1921). TET2 abnormalities were numbered according to the FM 992369 EMBL nucleotide sequence database. Previously annotated single nucleotide polymorphisms were not considered pathologic.

Figure 2.

Kaplan-Meier analysis of overall survival in patients in whom the TET2 mutation was analyzed at diagnosis. (A) Overall survival of 43 patients with either CMML1 or CMML2 according to the WHO classification (mutated TET2: 18 cases; non-mutated TET2: 25 cases). (B) Overall survival of the 29 patients with CMML1 in chronic phase according to the WHO classification (mutated TET2: 10 cases; non-mutated TET2: 19 cases).