BRD2 induces drug resistance through activation of the RasGRP1/Ras/ERK signaling pathway in adult T-cell lymphoblastic lymphoma.

Abstract

BACKGROUND:

Adult patients with T-cell lymphoblastic lymphoma (T-LBL) are treated with high-intensity chemotherapy regimens, but the response rate is still unsatisfactory because of frequent drug resistance. We aimed to investigate the potential mechanisms of drug resistance in adults with T-LBL.

METHODS:

Gene expression microarray was used to identify differential mRNA expression profiles between chemotherapy-resistant and chemotherapy-sensitive adult T-LBL tissues. Real-time PCR and immunohistochemistry were performed to detect the expression of bromodomain-containing protein 2 (BRD2) and c-Myc in fresh-frozen T-LBL tissues from 85 adult patients. The Ras pull-down assay was performed to monitor Ras activation. Chromatin immunoprecipitation assays were used to analyze the binding of E2F transcription factor 1 (E2F1)/BRD2 to the RAS guanyl releasing protein 1 (RasGRP1) promoter region. The drug resistance effect and mechanism of BRD2 were determined by both in vivo and in vitro studies.

RESULTS:

A total of 86 chemotherapy resistance-related genes in adult T-LBL were identified by gene expression microarray. Among them, BRD2 was upregulated in chemotherapy-resistant adult T-LBL tissues and associated with worse progression-free survival and overall survival of 85 adult T-LBL patients. Furthermore, BRD2 suppressed doxorubicin (Dox)-induced cell apoptosis both in vitro and in vivo. The activation of RasGRP1/Ras/ERK signaling might contribute to the Dox resistance effect of BRD2. Besides, OTX015, a bromodomain and extra-terminal (BET) inhibitor, reversed the Dox resistance effect of BRD2. Patient-derived tumor xenograft demonstrated that the sequential use of OTX015 after Dox showed superior therapeutic effects.

CONCLUSIONS:

Our data showed that BRD2 promotes drug resistance in adult T-LBL through the RasGRP1/Ras/ERK signaling pathway. Targeting BRD2 may be a novel strategy to improve the therapeutic efficacy and prolong survival of adults with T-LBL.

• Authors: Xiao-Peng Tian, Jun Cai, Shu-Yun Ma, Yu Fang, Hui-Qiang Huang, Tong-Yu Lin, Hui-Lan Rao, Mei Li, Zhong-Jun Xia, Tie-Bang Kang, Dan Xie, Qing-Qing Cai
• Journal: Cancer communications (London, England) (Cancer Commun (Lond)) Vol. 40 Issue 6 Pg. 245-259 (06 2020) ISSN: 2523-3548 [Electronic] United States
• PMID: 32459053 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.

Chemical References

• BRD2 protein, human
• DNA-Binding Proteins
• Guanine Nucleotide Exchange Factors
• RASGRP1 protein, human
• Transcription Factors
• Extracellular Signal-Regulated MAP Kinases
• ras Proteins

Topics

• Adult
• DNA-Binding Proteins (metabolism)
• Drug Resistance, Neoplasm
• Extracellular Signal-Regulated MAP Kinases
• Female
• Guanine Nucleotide Exchange Factors (metabolism)
• Humans
• Male
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics)
• Signal Transduction
• Transcription Factors (metabolism)
• ras Proteins