BCL6 locus is hypermethylated in angioimmunoblastic T-cell lymphoma
BCL6, a master transcription factor for differentiation of follicular helper T (TFH) cells, is highly expressed in angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphomas (PTCL) containing tumor cells with TFH features. TET2, encoding an epigenetic regulator, is frequently mutated in AITL/PTCL. We previously reported that Tet2 knockdown mice developed T-cell lymphomas with TFH features. Hypermethylation of the Bcl6 locus followed by BCL6 upregulation was thought to be the key event for lymphoma development in mice. The mechanisms by which BCL6 expression is upregulated in human AITL/PTCL, however, have not been elucidated. Here, we investigated the impact of TET2 mutations on methylation of BCL6 locus in human AITL/PTCL samples. Hypermethylation of the BCL6 locus was more frequent in PTCL samples than B-cell lymphoma samples (PTCL vs B-cell lymphomas: 9/42 vs 0/35). PTCL samples with TET2 mutations were more frequently hypermethylated than those without TET2 mutations (PTCL with TET2 mutations vs without mutations: 6/22 vs 0/17). BCL6 expression in hypermethylated samples was higher than that in low methylated samples. Deregulated BCL6 expression caused by hypermethylation and TET2 mutations may result in skewed TFH differentiation and eventually contribute to AITL/PTCL development in patients, as well as lymphoma development in Tet2 knockdown mice.
KeywordsAngioimmunoblastic T-cell lymphoma BCL6 expression Follicular helper T cells Hypermethylation TET2 mutation
This work was supported by the Grants-in-Aid for Scientific Research (KAKENHI: 16K15497 to M. S.-Y.; and 24390241, 25112703, and 15H01504 to S. C.) from the Ministry of Education, Culture, Sports, and Science of Japan. This work was also supported by Research Grants from the Daiichi Sankyo Foundation of Life Science and the Naito Foundation to M.S.-Y.; and The Uehara Memorial Foundation, Leukemia Research Fund, Takeda Science Foundation, and Kobayashi Foundation for Cancer Research to S.C.
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