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 S. Lossos, Salomon Amar, Yasodha Natkunam, Javier Briones, Ari Melnick, Raquel Malumbres, Jose A. Martinez-Climent

Research output: Contribution to journalArticle

22 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Hematology

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    Bertolo, C., Roa, S., Sagardoy, A., Mena-Varas, M., Robles, E. F., Martinez-Ferrandis, J. I., Sagaert, X., Tousseyn, T., Orta, A., Lossos, I. S., Amar, S., Natkunam, Y., Briones, J., Melnick, A., Malumbres, R., & 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