LITAF, a BCL6 target gene, regulates autophagy in mature B‐cell lymphomas. (25th June 2013)

• Record Type: Journal Article
• Authors: Bertolo, 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; Martinez‐Climent, Jose A.
• Is Part Of: British journal of haematology. Volume 162:Number 5(2013:Sep.)
• Page Start: 621
• Page End: 630
• Publication Date: 2013-06-25
• Subjects: Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.12440
• Languages: English
• ISSNs: 0007-1048

Abstract

<abstract abstract-type="main" id="bjh12440-abs-0001"> <title>Summary</title> <p>We have previously reported that <italic>LITAF</italic> 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 <italic>LITAF</italic> expression. Accordingly, <italic>BCL6</italic> silencing increased <italic>LITAF</italic> expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of <italic>LITAF</italic> 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 <italic>MAP1LC3B</italic> (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 <italic>LITAF</italic> silencing. Our results indicate that the BCL6‐mediated transcriptional repression of <italic>LITAF</italic> 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> </abstract>