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

Abstract

BackgroundAcquired 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 myelodysplastic syndromes. The present study was designed to determine the prevalence of TET2 gene alterations in chronic myelomonocytic leukemias. Design and MethodsBlood 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. ResultsWe 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. ConclusionsTET2 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.

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

“…These can broadly be divided into four categories: mutations involving epigenetic regulator genes such as EZH2, ASXL1, TET2, DNMT3A, IDH1, and IDH2 [9,10,14,27], mutations involving the spliceosome machinery such as SF3B1, SRSF2, U2AF35, ZRSR2, SF3A1, PRPF40B, U2AF65, and SF1 [13,14,19,20], mutations involving DNA damage response genes such as Tp53 [28], and mutations involving genes regulating cellular/receptor tyrosine kinases and (13) 12 (100) 9 (75) 3 (25) delP95R-R102-7 (8) 7 (100) 3 (43) 1 (14) R94-P95insR-1 (1) 1 ( (25) 5 (100) 5 (100) 0 (0) Q157G-1 (5) 0 (0) 0 (0) 1 (100) R158H-1 (5) 1 (100) 1 (100) 0 (0) CMML-1, chronic myelomonocytic leukemia-1; SF3B1, splicing factor 3B, subunit 1; SRSF2, serine/arginine-rich splicing factor 2; U2AF35, U2 small nuclear RNA auxiliary factor 1.…”

Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A

“…[10][11][12][13]49 However, a worse prognosis and acute transformation has been linked to ASXL1 mutations. 23 In contrast, the reports on the prognostic effect of TET2 mutations were controversial, 10,12,13 but our study suggests that they do not convey additional negative effects on prognosis, at least in this very homogenous and well-defined CMML cohort.…”

“…8,9 Recently, several genes have been found mutated in myeloid malignancies, including CMML. [10][11][12][13] These discoveries were facilitated by single nucleotide polymorphism array (SNP-A) karyotyping, which enables detection of somatic regions of copy number neutral loss of heterozygosity (CN-LOH), also called uniparental disomy (UPD). In CMML homozygous mutations in CBL and TET2 are associated with regions of UPD.…”

Molecular basis of myelodysplastic/myeloproliferative neoplasms

“…11,12 Other studies found TET2 mutations in 3 of 15 (20%), 14 6 of 17 (35%), 15 and 29 of 69 (42%) 16 of CMML patients, as well as 13 of 38 (34%) cases of aCML. 17 The largest series so far is reported in this issue of Haematologica by Kosmider et al 18 who…”