Adult T cell leukemia aggressivenness correlates with loss of both 5-hydroxymethylcytosine and TET2 expression

Abstract

Mutations in TET2, encoding one of the TET members responsible for the conversion of DNA cytosine methylation to hydroxymethylation (5-hmc), have been recently described in Human T-lymphotropic virus type 1-associated adult T-cell leukemia/lymphoma (ATLL). However, neither the amount of genomic 5-hmc in ATLL tumor cells nor TET2 expression has been studied yet. In this study, we analyzed these two parameters as well as the mutational status of TET2 in ATLL patients. By employing a direct in situ approach, we documented that tumor T cells infiltrating lymph nodes exhibit low level of 5-hmc compared to residual normal T cells. Furthermore, this 5-hmc defect was more pronounced in tumor T cells from acute patients than from chronic ones and correlated with reduced expression of TET2 protein. TET2 variations were found in 14 patients (20%), including 13 with aggressive forms. Strikingly, 9 of the 14 patients showed the same variation (SNP rs72963007), whose frequency in ATLL patients was significantly higher than that of an ethnically matched control population (13% vs. 5%). However, no reduction of 5-hmc was found in PBMC from individuals possessing the variant rs72963007 TET2 allele, as compared to wild-type individuals. In contrast, a robust correlation was observed between 5-hmc and the levels of TET2 mRNA. Finally, loss of 5-hmc and TET2 downregulation both correlated with poor survival. These findings demonstrate that ATLL progression coincides with loss of genomic 5-hmc and indicate that downregulation of TET2, rather than TET2 mutations, is the key mechanism involved in 5-hmc modulation during ATLL progression.

Low expression of TET2 gene in pediatric acute lymphoblastic leukemia is associated with poor clinical outcome

“…It is shown that the mutation of epigenetic related genes ( TET2 , IDH1/2 , WT1 and DNMT3A ) in cases may lose 5‐hmC expression, reflecting the relationship between the epigenetic pathway dysfunction and leukemia . Low expression of TET2 has been reported in several types of hematologic malignancies in adult patients . In the present study, we have studied TET2 mRNA levels in BM samples from children with newly diagnosed ALL and compared them to the levels obtained from control samples with nonmalignant hematopoietic diseases.…”

“…The decrease in TET2 expression leads to an increase in the number of hematopoietic stem cells (HSCs) and enhances their self‐renewal ability. TET2 gene mutation was found in myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), acute myeloid leukemia (AML), acute T‐lymphocytic leukemia (T‐ALL), and chronic myeloid leukemia (CML) as well as chronic myelomonocytic leukemia (CMML) in adult patients . Some clinical reports have shown that TET2 mutations are associated with poor prognosis in patients.…”

Correlation of TET2 SNP rs2454206 with improved survival in children with acute myeloid leukemia featuring intermediate‐risk cytogenetics

“…TET2 mutations are common in adult myeloid malignancies including AML and myelodysplastic syndrome but rare in childhood AML with a frequency of about 2% . Some studies show that TET2 mutations or SNPs do not result in detectable changes of global genomic 5‐hydroxymethylcytosine levels . Data on the influence of TET2 mutations on adult AML are currently inconclusive, although association of TET2 mutations with an inferior outcome in intermediate‐risk cytogenetics AML has been reported in the literature .…”

“…However, our study revealed no correlation between TET2 SNP rs2454206 genotype and TET2 expression levels. In their study of the effect of TET2 SNP rs72963007 on adult T cell leukemia, Macais and colleague detected no difference in TET2 expression levels between patients with different TET2 SNP genotypes . Furthermore, TET2 SNP rs72963007 has been shown to be independent of TET2 expression in adult chronic lymphocytic leukemia .…”

“…However, our study revealed no correlation between TET2 SNP rs2454206 genotype and TET2 expression levels. In their study of the effect of TET2 SNP rs72963007 on adult T cell leukemia, Macais and colleague detected no difference in TET2 expression levels between patients with different TET2 SNP genotypes 30. Furthermore,FIG URE 2 Kaplan-Meier plots of OS and EFS for AML with TET2 SNP rs2454206 AA and 2454206 GG/GA in the intermediate-risk cytogenetics (A, B, 5-year OS and EFS), and CN-AML (C, D, 5-year OS and EFS)…”