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

Abstract

BackgroundAdult 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.MethodsGene 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.ResultsA 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.ConclusionsOur 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.