Pan-HDAC Inhibitors May Restore PRDM1 Expression in Follicular Lymphoma
Authors: Fest Thierry , Desmots-Loyer Fabienne , Roussel Mikael , Pangault Celine , Pastoret Cedric , Llamas-Gutierrez Francisco , Guiheneuf Eric , Camara-clayette Valérie , Lamy Thierry , Tarte Karin , Ribrag Vincent 
Published: October 2019

Follicular lymphoma (FL) arises from a germinal center (GC) B cell proliferation supported by a bidirectional crosstalk with tumor microenvironment, in particular with follicular helper T cells (Tfh). Besides BCL2 translocation hallmark, tumor B cells progressively acquire loss-of-function alterations within chromatin organization factor genes. Notably, frequent inactivating mutations in CREBBP acetyltransferase are found in B-cell lymphoma and drive deep epigenetic and transcriptional profile modifications. Our transcriptional analysis on highly purified cell fractions revealed that, conversely to normal GC B cells (centroblasts and centrocytes), primary FL B cells are unable to upregulate the transcription repressor PRDM1 that is required for plasma cell differentiation and maintenance. This defect happens although FL tumor environment is enriched in the potent inducer of PRDM1, IL-21 that we found highly produced by CD4+ Tfhs.

In 20 different FLs perfectly characterized at clinical and genetic level, we analyzed their FL cells obtained after purification from the initial tumor. Globally, we found a significant lack of IL-21-mediated PRDM1 response while our control cell line showed a positive increase of PRDM1 expression. We analyzed some of these primary FL tumor cells by qPCR-ChIP to assess BCL6 protein binding at intron 3 of the PRDM1 gene. We found that the lack of PRDM1 response to IL-21 was associated with an abnormal increased enrichment of the BCL6 protein repressor in PRDM1 gene. Our data indicated this was especially the case for FLs with nonfunctional CREBBP. We next explored 6 FLs, cells were treated in vitro with vorinostat, a pan-HDAC inhibitor. We found that for FL B cells carrying CREBBP loss-of-function mutations, vorinostat restored partially their PRDM1 response to IL-21 by lowering BCL6 bound to PRDM1. Finally, we wanted to assess this drug effect in the context of FL patients treated with a pan-HDACi. We found 4 patients involved in a phase I/II clinical at the Gustave Roussy Institute in Villejuif and treated with abexinostat, a new and off-label pan-HDAC inhibitor. All the patients presented a progressive FL disease, were heavily pretreated and their tumor were characterized by genomic DNA sequencing. One patient reached a stable complete remission, the drug was discontinued after 4 years of treatment. Among the three other patients, one had an objective 28-month response to the drug before relapse, one a stable disease for seven months while the last one did not response to the drug. For these 3 patients we've got fine needle tumor biopsy when patients re-progressed. Re-biopsies showed an increased expression of plasma cell-identity genes, mainly PRDM1 and XBP1, which underline the progression of FL B cells in the process of differentiation. Altogether, our data uncover a new mechanism by which pan-HDAC inhibitors may act positively to treat FL patients.

Disclosures

Ribrag: BMS: Consultancy, Honoraria, Other: travel; argenX: Research Funding; Servier: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Research Funding; Roche: Honoraria, Other: travel; Incyte Corporation: Consultancy; pharmamar: Other: travel; Infinity: Consultancy, Honoraria; MSD: Honoraria.