Identification of a novel BET bromodomain inhibitor-sensitive, gene regulatory circuit that controls Rituximab response and tumour growth in aggressive lymphoid cancers

Anouk Emadali, Sophie Rousseaux, Juliana Bruder-Costa, Claire Rome, Samuel Duley, Sieme Hamaidia, Patricia Betton, Alexandra Debernardi, Dominique Leroux, Benoit Bernay, Sylvie Kieffer-Jaquinod, Florence Combes, Elena Ferri, Charles E McKenna, Carlo Petosa, Christophe Bruley, Jérôme Garin, Myriam Ferro, Rémy Gressin, Mary B Callanan, Saadi Khochbin, Anouk Emadali, Sophie Rousseaux, Juliana Bruder-Costa, Claire Rome, Samuel Duley, Sieme Hamaidia, Patricia Betton, Alexandra Debernardi, Dominique Leroux, Benoit Bernay, Sylvie Kieffer-Jaquinod, Florence Combes, Elena Ferri, Charles E McKenna, Carlo Petosa, Christophe Bruley, Jérôme Garin, Myriam Ferro, Rémy Gressin, Mary B Callanan, Saadi Khochbin

Abstract

Immuno-chemotherapy elicit high response rates in B-cell non-Hodgkin lymphoma but heterogeneity in response duration is observed, with some patients achieving cure and others showing refractory disease or relapse. Using a transcriptome-powered targeted proteomics screen, we discovered a gene regulatory circuit involving the nuclear factor CYCLON which characterizes aggressive disease and resistance to the anti-CD20 monoclonal antibody, Rituximab, in high-risk B-cell lymphoma. CYCLON knockdown was found to inhibit the aggressivity of MYC-overexpressing tumours in mice and to modulate gene expression programs of biological relevance to lymphoma. Furthermore, CYCLON knockdown increased the sensitivity of human lymphoma B cells to Rituximab in vitro and in vivo. Strikingly, this effect could be mimicked by in vitro treatment of lymphoma B cells with a small molecule inhibitor for BET bromodomain proteins (JQ1). In summary, this work has identified CYCLON as a new MYC cooperating factor that autonomously drives aggressive tumour growth and Rituximab resistance in lymphoma. This resistance mechanism is amenable to next-generation epigenetic therapy by BET bromodomain inhibition, thereby providing a new combination therapy rationale for high-risk lymphoma.

Keywords: CCDC86; CD40; R-CHOP; cancer-testis factor; double-hit B-cell non-Hodgkin's lymphoma.

© 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Figures

Figure 1
Figure 1
Proteomics-based discovery strategy for identification of abnormally expressed nuclear factors in lymphoma

  1. Schematic representation of the overall experimental strategy, as indicated. NAS: nuclear acid-soluble, MS: mass spectrometry.

  2. Heat-map representation of the gene expression levels for 6 candidate ‘off-context’ genes in normal lymphoid and non-lymphoid tissues; PB: peripheral blood [data from BioGPS (Su et al, 2004)].

  3. Heat-map representation of gene expression profiles for 5 ‘off-context’ genes, as indicated; NHL: non-Hodgkin lymphoma, B-CLL: B-cell chronic lymphocytic leukemia, FL: follicular lymphoma, HCL: hairy cell leukemia, MCL: mantle cell lymphoma, BL: Burkitt lymphoma, DLBCL: diffuse large B-cell lymphoma, PEL: primary effusion lymphoma [data from GEO GSE2350 (Basso et al, 2005)].

Figure 2
Figure 2
CYCLON overexpression is a feature of aggressive NHL and correlates to adverse clinical outcome in DLBCL

  1. Kaplan–Meier cumulative survival curves in DLBCL patients from GEO GSE10846 (Lenz et al, 2008) according to CYCLON expression level (high: above 3rd quartile and low: below 1st quartile, respectively), p values from log-rank test.

  2. Survival curves according to CYCLON expression levels in DLBCL patients treated by Rituximab-CHOP (left panel, R-CHOP) or CHOP alone (right panel), p-values from log-rank test.

  3. Survival curves according to CYCLON expression levels in ABC or GCB DLBCL patients treated by Rituximab-CHOP, p-values from log-rank test.

  4. RT-qPCR and western blot (upper panel) analysis of CYCLON expression in normal lymphoid and non-lymphoid tissues, and in lymphoma lines, as indicated: PB B: peripheral blood B cells, LN: lymph node, BM: bone marrow, n = 3.

  5. Affymetrix-derived CYCLON gene expression values for individual patients from GEO GSE2350 (Basso et al, 2005), p-value from Wilcoxon test (E) and GEO GSE10846 (Lenz et al, 2008) (F).

Figure 3
Figure 3
CYCLON is a MYC target involved in lymphoma progression in vivo

  1. Analysis by RT-qPCR and western blot (upper and lower panels, respectively) of CYCLON expression in control and MYC-knockdown Raji lymphoma B cells, n = 3.

  2. CYCLON gene expression values in the MYC-inducible cell line, P493 (Schlosser et al, 2005).

  3. Affymetrix-derived MYC gene expression values for DLBCL in GEO GSE10846 (Lenz et al, 2008) and GEO GSE4475 (Hummel et al, 2006); high CYCLON expression: above 3rd quartile; low CYCLON expression: below 1st quartile, p-values from Student t test.

  4. Kaplan–Meier cumulative survival curves for xenotransplanted mice bearing tumours derived from Raji shCtrl and Raji shCYCLON cell lines, p-value from log-rank test.

  5. Tumour weight (28 days post-injection) for xenotransplanted mice bearing tumours derived from Raji shCtrl and Raji shCYCLON cell lines, n = 11 for each group, p-value from Wilcoxon test (left) and bioluminescence imaging for 4 representative mice (right).

Figure 4
Figure 4
CYCLON regulates gene signatures associated with B-cell differentiation and proliferation

  1. Gene Set Enrichment Analysis (GSEA) enrichment plots obtained from gene expression data from CYCLON knockdown Raji cells (shCYCLON, n = 4) compared to control Raji cells (shCTRL, n = 4) with associated heat-maps (left). GSEA enrichment plots show down-regulation of aggressive multiple myeloma signature (A) and up-regulation of a CD40-dependent B-cell signature (B) in CYCLON knock-down compared to control Raji lymphoma B cells. Genes are ordered on the x axis by their differential expression score (each vertical line representing a gene).

  2. Top 50 genes up-regulated (red) or down-regulated (blue) upon CYCLON knockdown (shCYCLON) in Raji lymphoma B cells compared to control (shCtrl). Gene sets are from MSIGDB collection. See the Materials and Methods section and supplementary material for detailed data analysis.

  3. Heat-map representation of co-regulated genes upon CYCLON knockdown and JQ1 treatment in Raji cells (data from GSE29449, Mertz et al, 2011).

  4. Venn diagram showing the overlap between differentially expressed genes upon CYCLON knockdown and JQ1 treatment in Raji cells (data from GSE29449, Mertz et al, 2011) and list of commonly down- and up-regulated genes. Black and green arrows: genes cited in text. Green arrows refer to genes commonly regulated by CYCLON and JQ1 within the CD40 signature.

Figure 5
Figure 5
CYCLON-mediated resistance to Rituximab in BL and MYC-overexpressing DLBCL

  1. Western Blot analysis of CYCLON, MYC and histone H3 (as loading control) expression in levels in a panel of BL and DLBCL cell lines.

  2. Evaluation of basal Rituximab sensitivity using CDC (complement dependent cytoxicity) in the presence (+cplt) or absence of human complement (−cplt) (B) and Rituximab-induced direct killing (C) assays as described in the Materials and Methods section, n = 6.

  3. Flow cytometry analysis of CD20 expression in a panel of BL and DLBCL cell lines, n = 3.

  4. Rituximab (E: CDC; F: direct killing) sensitivity of CYCLON knockdown (shCYCLON) Raji (BL), B593, SUDHL4 and OCI-Ly3 (DLBCL) lymphoma B cells compared to controls (shCtrl); p values from a Wilcoxon test, n = 8 for each cell line, ns: non-significant.

  5. Left panel: bioluminescence imaging of Rituximab response (200 µg/day of Rituximab) in SCID mice xenotransplanted with shCtrl or CYCLON knockdown Raji lymphoma as indicated compared to control-treated mice (IgG for 14 days). Right panel: Relative tumour growth at days 0, 7 and 14, as indicated; p-value from a Wilcoxon test, n = 6 for each group.[Correction added after publication on 4 July 2013: The figure title “CYCLON-mediated increase in Rituximab sensitivity in BL and MYC-dependent DLBCL” was corrected to “CYCLON-mediated resistance to Rituximab in BL and MYC-overexpressing DLBCL”]

Figure 6
Figure 6
BET bromodomain inhibition overrides CYCLON-mediated Rituximab resistance

  1. Western Blot analysis of CYCLON, MYC and H3 expression (as loading control) in lymphoma B cells treated for 24 h with control DMSO (0) or increasing doses of JQ1 as mentioned, n = 3.

  2. Western Blot analysis of CYCLON, MYC and H3 expression (as loading control) in lymphoma B cells treated with control DMSO (0) or 500 nM JQ1 for the indicated times after treatment and wash-out, n = 3.

  3. Rituximab (CDC, C; direct killing, D) sensitivity assays of lymphoma B cells after 24 h treatment with control DMSO (JQ1-) or 1 µ JQ1 pre-treatment performed as described in Fig 4E, F; p-values from a Wilcoxon test, n = 4 for each cell line, ns: non-significant.

  4. Evaluation of Rituximab sensitivity (CDC) of Raji cells pre-treated for 24 h with control DMSO (0) or increasing doses of JQ1 as mentioned, n = 3 for each cell line.

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