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Clin Cancer Res. 2015 Jan 1;21(1):113-22. doi: 10.1158/1078-0432.CCR-13-3346. Epub 2014 Jul 9.

Inhibition of bromodomain proteins for the treatment of human diffuse large B-cell lymphoma.

Author information

1
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
2
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts.
3
Division of Hematology and Oncology, Tufts Medical Center, Boston, Massachusetts.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5
The Jackson Laboratory, Bar Harbor, Maine.
6
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
7
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts. hong.zhang@umassmed.edu.

Abstract

PURPOSE:

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.

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 patients with DLBCL, 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 use in the treatment of DLBCL.

PMID:
25009295
PMCID:
PMC4286476
DOI:
10.1158/1078-0432.CCR-13-3346
[Indexed for MEDLINE]
Free PMC Article

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