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LITAF , a BCL 6 target gene, regulates autophagy in mature B‐cell lymphomas
Author(s) -
Bertolo Cristina,
Roa Sergio,
Sagardoy Ainara,
MenaVaras Maria,
Robles Eloy F.,
MartinezFerrandis Jose I.,
Sagaert Xavier,
Tousseyn Thomas,
Orta Alberto,
Lossos Izidore S.,
Amar Salomon,
Natkunam Yasodha,
Briones Javier,
Melnick Ari,
Malumbres Raquel,
MartinezCliment Jose A.
Publication year - 2013
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12440
Subject(s) - bcl6 , gene silencing , biology , cancer research , autophagy , b cell , germinal center , microbiology and biotechnology , gene , genetics , apoptosis , antibody
Summary 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 BCL 6 show opposite expression in tonsil B‐cell subpopulations and B‐cell lymphomas, suggesting that BCL 6 may regulate LITAF expression. Accordingly, BCL 6 silencing increased LITAF expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of LITAF by BCL 6. 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 MAP 1 LC 3B ( LC 3B). 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 BCL 6‐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 BCL 6‐driven lymphomas may contribute to lymphomagenesis.