Inhibition of bromodomain proteins for the treatment of human diffuse large B-cell lymphoma
Department of Cell and Developmental Biology; Department of Cancer Biology
Cancer Biology | Neoplasms | Oncology
Purpose: Approximately 50% of patients with diffuse large B-cell lymphoma (DLBCL) enter long-term remission after standard chemotherapy. DLBCL patients who do not respond to chemotherapy have few treatment options. There remains a critical need to identify effective and targeted therapeutics for DLBCL.
Experimental Design: 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 DLBCL patients, suggesting that c-MYC is a compelling target for DLBCL therapy. The small molecule JQ1 suppresses c-MYC 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 in vivo.
Results: 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 G1 arrest induced by JQ1 treatment in DLBCL cells was followed by either apoptosis or senescence. The expression of c-MYC 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.
Conclusion: Our results demonstrate that inhibition of the BET family of bromodomain proteins by JQ1 has potential clinical utility in the treatment of DLBCL.
diffuse large B-cell lymphoma, c-MYC, apoptosis, senescence, JQ1
DOI of Published Version
Trabucco SE, Gerstein RM, Evens AM, Bradner JE, Shultz LD, Greiner DL, Zhang H. Inhibition of bromodomain proteins for the treatment of human diffuse large B-cell lymphoma. Clin Cancer Res. 2014 Jul 9. doi: 10.1158/1078-0432.CCR-13-3346. [Epub ahead of print] Link to article on publisher's website
Clinical Cancer Research
Trabucco SE, Gerstein RM, Evens AM, Brander JE, Shultz LD, Greiner D, Zhang H. (2014). Inhibition of bromodomain proteins for the treatment of human diffuse large B-cell lymphoma. GSBS Student Publications. https://doi.org/10.1158/1078-0432.CCR-13-3346. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1861