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Aug 2017 Oncotarget

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


Marçais A, Waast L, Bruneau J, Hanssens K, Asnafi V, Gaulard P, Suarez F, Dubreuil P, Gessain A, Hermine O, Pique C


Mutations in , 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 in ATLL patients. By employing a direct 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. 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 allele, as compared to wild-type individuals. In contrast, a robust correlation was observed between 5-hmc and the levels of 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 , rather than mutations, is the key mechanism involved in 5-hmc modulation during ATLL progression.

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