{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T14:33:30Z","timestamp":1793370810483,"version":"4.5.0"},"reference-count":39,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"6","license":[{"start":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T00:00:00Z","timestamp":1590537600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Special Support Program of Sun Yat\u2010sen University Cancer Center"},{"name":"Special Support Program of Sun Yat-sen University Cancer Center"},{"name":"National Key R&D Program of China"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Commun"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Adult patients with T\u2010cell lymphoblastic lymphoma (T\u2010LBL) are treated with high\u2010intensity 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\u2010LBL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Gene expression microarray was used to identify differential mRNA expression profiles between chemotherapy\u2010resistant and chemotherapy\u2010sensitive adult T\u2010LBL tissues. Real\u2010time PCR and immunohistochemistry were performed to detect the expression of bromodomain\u2010containing protein 2 (BRD2) and c\u2010Myc in fresh\u2010frozen T\u2010LBL tissues from 85 adult patients. The Ras pull\u2010down 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\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      A total of 86 chemotherapy resistance\u2010related genes in adult T\u2010LBL were identified by gene expression microarray. Among them, BRD2 was upregulated in chemotherapy\u2010resistant adult T\u2010LBL tissues and associated with worse progression\u2010free survival and overall survival of 85 adult T\u2010LBL patients. Furthermore, BRD2 suppressed doxorubicin (Dox)\u2010induced cell apoptosis both\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      . The activation of RasGRP1\/Ras\/ERK signaling might contribute to the Dox resistance effect of BRD2. Besides, OTX015, a bromodomain and extra\u2010terminal (BET) inhibitor, reversed the Dox resistance effect of BRD2. Patient\u2010derived tumor xenograft demonstrated that the sequential use of OTX015 after Dox showed superior therapeutic effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Our data showed that BRD2 promotes drug resistance in adult T\u2010LBL 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\u2010LBL.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.12039","type":"journal-article","created":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T07:21:39Z","timestamp":1590564099000},"page":"245-259","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["BRD2 induces drug resistance through activation of the RasGRP1\/Ras\/ERK signaling pathway in adult T\u2010cell lymphoblastic lymphoma"],"prefix":"10.34133","volume":"40","author":[{"given":"Xiao\u2010Peng","family":"Tian","sequence":"first","affiliation":[{"name":"Sun Yat\u2010sen University Cancer Center","place":["Guangzhou, P. R. China"]},{"name":"Sun Yat\u2010sen University Cancer Center","place":["Guangzhou, P. R. 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