Abstract
<div>Abstract<p><b>Purpose:</b> Approximately 50% of patients with diffuse large B-cell lymphoma (DLBCL) enter long-term remission after standard chemotherapy. Patients with DLBCL who do not respond to chemotherapy have few treatment options. There remains a critical need to identify effective and targeted therapeutics for DLBCL.</p><p><b>Experimental Design:</b> Recent studies have highlighted the incidence of increased c-MYC protein in DLBCL and the correlation between high levels of c-MYC protein and poor survival prognosis of patients with DLBCL, suggesting that c-MYC is a compelling target for DLBCL therapy. The small molecule JQ1 suppresses <i>c-MYC</i> expression through inhibition of the bromodomain and extra-terminal (BET) family of bromodomain proteins. We investigated whether JQ1 can inhibit proliferation of DLBCL cells in culture and xenograft models <i>in vivo</i>.</p><p><b>Results:</b> We show that JQ1 at nanomolar concentrations efficiently inhibited proliferation of human DLBCL cells in a dose-dependent manner regardless of their molecular subtypes, suggesting a broad effect of JQ1 in DLBCL. The initial G<sub>1</sub> arrest induced by JQ1 treatment in DLBCL cells was followed by either apoptosis or senescence. The expression of <i>c-MYC</i> was suppressed as a result of JQ1 treatment from the natural, chromosomally translocated, or amplified loci. Furthermore, JQ1 treatment significantly suppressed growth of DLBCL cells engrafted in mice and improved survival of engrafted mice.</p><p><b>Conclusion:</b> Our results demonstrate that inhibition of the BET family of bromodomain proteins by JQ1 has potential clinical use in the treatment of DLBCL. <i>Clin Cancer Res; 21(1); 113–22. ©2014 AACR</i>.</p><p><i>See related commentary by Mottok and Gascoyne, p. 4</i></p></div>
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