TY - JOUR
T1 - LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas
AU - Bertolo, Cristina
AU - Roa, Sergio
AU - Sagardoy, Ainara
AU - Mena-Varas, Maria
AU - Robles, Eloy F.
AU - Martinez-Ferrandis, Jose I.
AU - Sagaert, Xavier
AU - Tousseyn, Thomas
AU - Orta, Alberto
AU - Lossos, Izidore S.
AU - Amar, Salomon
AU - Natkunam, Yasodha
AU - Briones, Javier
AU - Melnick, Ari
AU - Malumbres, Raquel
AU - Martinez-Climent, Jose A.
PY - 2013/9/1
Y1 - 2013/9/1
N2 - 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. © 2013 John Wiley & Sons Ltd.
AB - 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. © 2013 John Wiley & Sons Ltd.
KW - Autophagy
KW - B cells
KW - Germinal centre
KW - Non-hodgkin lymphoma
KW - Transcription factors
U2 - 10.1111/bjh.12440
DO - 10.1111/bjh.12440
M3 - Article
SN - 0007-1048
VL - 162
SP - 621
EP - 630
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 5
ER -