Pan-HDAC inhibitors restore PRDM1response to IL-21 in CREBBP mutated follicular lymphoma

Purpose: Follicular lymphoma (FL) arises from a germinal center B-cell proliferation supported by a bidirectional crosstalk with tumor microenvironment, in particular with follicular helper T cells (Tfh). We explored the relation that exist between the differentiation arrest of FL cells and loss-of-function of CREBBP acetyltransferase. Experimental design: The study used human primary cells obtained from either, FL tumors characterized for somatic mutations, or inflamed tonsils for normal germinal center B cells. Transcriptome and functional analyses were done to decipher the B and T cell crosstalk. Responses assessed by flow cytometry and molecular biology including ChIP-qPCR approaches. Results: Conversely to normal B cells, FL cells are unable to upregulate the transcription repressor PRDM1, required for plasma cell differentiation. This defect occurs although the FL microenvironment is enriched in the potent inducer of PRDM1, IL-21, highly produced by Tfhs. In FL carrying CREBBP loss-of-function mutations, we found a lack of IL-21-mediated PRDM1 response associated with an abnormal increased enrichment of the BCL6 protein repressor in PRDM1gene. Moreover, in these FL cells, pan-HDAC inhibitor Vorinostat restored their PRDM1 response to IL-21 by lowering BCL6 bound to PRDM1. This finding was reinforced by our exploration of FL patients treated with another pan-HDAC inhibitor. Patients showed an increase of plasma cell-identity genes, mainly PRDM1and XBP1, which underline the progression of FL B cells in the differentiation process. Conclusion: Our data uncover a new mechanism by which pan-HDAC inhibitors may act positively to treat FL patients through the induction of the expression of plasma cell genes.

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