Télévie: Targeting methylation as therapy for adult T cell leukemia/lymphoma

There is currently no satisfactory treatment against human T-lymphotropic virus type 1 (HTLV-1) induced adult T cell leukemia/lymphoma (ATLL). A major problem is lack of viral expression leading to escape from destruction by the host' immune response. In fact, the 5'LTR promoter is frequently silenced by cytosine methylation. Our previous studies have demonstrated that lysine deacetylase inhibitors such as valproic acid (VPA) can induce viral expression. Although VPA treatment is well tolerated in patients, its effect on the proviral loads is unfortunately transient. Therefore, we propose in this project to target another epigenetic modification: methylation of cytosines and lysines (histones and non-histone proteins). Our project,
which focuses on the structure of human DNA methyltransferases (DNMT3A/B), aims at identifying and characterizing ligands of the catalytic (cat-DNMT3) and regulatory (PWWP-DNMT3 and ADD-DNMT3) domains. Compounds identified in this project will be helpful as pharmacologic tools allowing a better understanding of the basic mechanisms of DNA methylation and the interplay with other epigenetic processes such as acetylation and histone methylation. These compounds could also be instrumental as chemotherapeutic agents against ATLL.