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

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

Edité par CCSD ; Wiley Open Access -

International audience. 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.

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