LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas

Cristina Bertolo, Sergio Roa, Ainara Sagardoy, Maria Mena-Varas, Eloy F. Robles, Jose I. Martinez-Ferrandis, Xavier Sagaert, Thomas Tousseyn, Alberto Orta, Izidore Lossos, Salomon Amar, Yasodha Natkunam, Javier Briones, Ari Melnick, Raquel Malumbres, Jose A. Martinez-Climent

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)621-630
Number of pages10
JournalBritish Journal of Haematology
Volume162
Issue number5
DOIs
StatePublished - Sep 1 2013

Fingerprint

Autophagy
B-Cell Lymphoma
B-Lymphocytes
Germinal Center
Genes
Lipopolysaccharides
Tumor Necrosis Factor-alpha
Gene Expression
Chromatin Immunoprecipitation
Palatine Tonsil
Starvation
Luciferases
Fluorescent Antibody Technique
Monocytes
Lymphoma
Cell Line

Keywords

  • Autophagy
  • B cells
  • Germinal centre
  • Non-hodgkin lymphoma
  • Transcription factors

ASJC Scopus subject areas

  • Hematology

Cite this

Bertolo, C., Roa, S., Sagardoy, A., Mena-Varas, M., Robles, E. F., Martinez-Ferrandis, J. I., ... Martinez-Climent, J. A. (2013). LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas. British Journal of Haematology, 162(5), 621-630. https://doi.org/10.1111/bjh.12440

LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas. / Bertolo, Cristina; Roa, Sergio; Sagardoy, Ainara; Mena-Varas, Maria; Robles, Eloy F.; Martinez-Ferrandis, Jose I.; Sagaert, Xavier; Tousseyn, Thomas; Orta, Alberto; Lossos, Izidore; Amar, Salomon; Natkunam, Yasodha; Briones, Javier; Melnick, Ari; Malumbres, Raquel; Martinez-Climent, Jose A.

In: British Journal of Haematology, Vol. 162, No. 5, 01.09.2013, p. 621-630.

Research output: Contribution to journalArticle

Bertolo, C, Roa, S, Sagardoy, A, Mena-Varas, M, Robles, EF, Martinez-Ferrandis, JI, Sagaert, X, Tousseyn, T, Orta, A, Lossos, I, Amar, S, Natkunam, Y, Briones, J, Melnick, A, Malumbres, R & Martinez-Climent, JA 2013, 'LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas', British Journal of Haematology, vol. 162, no. 5, pp. 621-630. https://doi.org/10.1111/bjh.12440
Bertolo C, Roa S, Sagardoy A, Mena-Varas M, Robles EF, Martinez-Ferrandis JI et al. LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas. British Journal of Haematology. 2013 Sep 1;162(5):621-630. https://doi.org/10.1111/bjh.12440
Bertolo, Cristina ; Roa, Sergio ; Sagardoy, Ainara ; Mena-Varas, Maria ; Robles, Eloy F. ; Martinez-Ferrandis, Jose I. ; Sagaert, Xavier ; Tousseyn, Thomas ; Orta, Alberto ; Lossos, Izidore ; Amar, Salomon ; Natkunam, Yasodha ; Briones, Javier ; Melnick, Ari ; Malumbres, Raquel ; Martinez-Climent, Jose A. / LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas. In: British Journal of Haematology. 2013 ; Vol. 162, No. 5. pp. 621-630.
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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

AU - Amar, Salomon

AU - Natkunam, Yasodha

AU - Briones, Javier

AU - Melnick, Ari

AU - Malumbres, Raquel

AU - Martinez-Climent, Jose A.

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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.

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.

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