TitleLITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas.
Publication TypeJournal Article
Year of Publication2013
AuthorsBertolo, Cristina, Roa Sergio, Sagardoy Ainara, Mena-Varas Maria, Robles Eloy F., Martinez-Ferrandis Jose I., Sagaert Xavier, Tousseyn Thomas, Orta Alberto, Lossos Izidore S., Amar Salomon, Natkunam Yasodha, Briones Javier, Melnick Ari, Malumbres Raquel, and Martinez-Climent Jose A.
JournalBr J Haematol
Date Published2013 Sep
KeywordsAutophagy, B-Lymphocyte Subsets, Cell Line, Tumor, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Humans, Introns, Lymphoma, B-Cell, Neoplasm Proteins, Nuclear Proteins, Proto-Oncogene Proteins c-bcl-6, Transcription Factors, Transcription, Genetic, Tumor Necrosis Factor-alpha

<p>We have previously reported that LITAF is silenced by promoter hypermethylation in germinal centre-derived B-cell lymphomas, but beyond these data the regulation and function of lipopolysaccharide-induced tumour necrosis factor (TNF) factor (LITAF) in B cells are unknown. Gene expression and immunohistochemical studies revealed that LITAF and BCL6 show opposite expression in tonsil B-cell subpopulations and B-cell lymphomas, suggesting that BCL6 may regulate LITAF expression. Accordingly, BCL6 silencing increased LITAF expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of LITAF by BCL6. Gain- and loss-of-function experiments in different B-cell lymphoma cell lines revealed that, in contrast to its function in monocytes, LITAF does not induce lipopolysaccharide-mediated TNF secretion in B cells. However, gene expression microarrays defined a LITAF-related transcriptional signature containing genes regulating autophagy, including MAP1LC3B (LC3B). In addition, immunofluorescence analysis co-localized LITAF with autophagosomes, further suggesting a possible role in autophagy modulation. Accordingly, ectopic LITAF expression in B-cell lymphoma cells enhanced autophagy responses to starvation, which were impaired upon LITAF silencing. Our results indicate that the BCL6-mediated transcriptional repression of LITAF may inhibit autophagy in B cells during the germinal centre reaction, and suggest that the constitutive repression of autophagy responses in BCL6-driven lymphomas may contribute to lymphomagenesis.</p>

Alternate JournalBr J Haematol
PubMed ID23795761
PubMed Central IDPMC4111142
Grant ListR01 CA104348 / CA / NCI NIH HHS / United States
R01 DE014079 / DE / NIDCR NIH HHS / United States