AID and TET2 co ‐operation modulates FANCA expression by active demethylation in diffuse large B cell lymphoma

(i) AID recruits TET2 to bind FANCA promoter; (ii) AID ‐TET2 complex demethylate FANCA and increase its expression in DLBCL; (iii) A combination of proteasome inhibitor bortezomib with AID and TET2 depletion significantly inhibits DLBCL cell growth. SummaryDiffuse large B cell lymphoma (DLBCL) is traced to a mature B malignance carrying abnormal activation ‐induced cytidine deaminase (AID) expression. AID activity initially focuses on deamination of cytidine to uracil to generate somatic hypermutation and class‐switch recombination of the immunoglobulin (Ig), but recently it has been implicated in DNA demethylation of genes required for B cell dev elopment and proliferation in the germinal centre (GC). However, whether AID activity on mutation or demethylation of genes involves oncogenesis of DLBCL has not been well characterized. Our data demonstrate that the proto‐oncogene Fanconi anaemia complementation group A (FANCA) is highly expressed in DLBCL patients and cell lines, respectively. AID recruits demethylation enzyme ten eleven translocation family member (TET2) to bind theFANCA promoter. As a result,FANCA is demethylated and its expression increases in DLBCL. On the basis of our findings, we have developed a new therapeutic strategy to significantly inhibit DLBCL cell growth by combination of the proteasome inhibitor bortezomib with AID and TET2 depletion. These findings support a novel mechanism that AID has a crucial role in active demethylation for oncogene a...
Source: Clinical and Experimental Immunology - Category: Allergy & Immunology Authors: Tags: Original Article Source Type: research