NDLI: BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting 'Undruggable' Myc-pathway genes

Content Provider	Springer Nature : BioMed Central
Author	Wu, Shuiyan Jiang, You Hong, Yi Chu, Xinran Zhang, Zimu Tao, Yanfang Fan, Ziwei Bai, Zhenjiang Li, Xiaolu Chen, Yanling Li, Zhiheng Ding, Xin Lv, Haitao Du, Xiaoli Lim, Su Lin Zhang, Yongping Huang, Saihu Lu, Jun Pan, Jian Hu, Shaoyan
Abstract	Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL. Methods Expression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP). Results BRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo. Conclusions BRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.
Related Links	https://cancerci.biomedcentral.com/counter/pdf/10.1186/s12935-021-01908-w.pdf
Ending Page	16
Page Count	16
Starting Page	1
File Format	HTM / HTML
ISSN	14752867
DOI	10.1186/s12935-021-01908-w
Journal	Cancer Cell International
Issue Number	1
Volume Number	21
Language	English
Publisher	BioMed Central
Publisher Date	2021-04-22
Access Restriction	Open
Subject Keyword	Cancer Research Cell Biology BRD4 ARV-825 T-cell acute lymphoblastic leukemia Pediatric C-Myc
Content Type	Text
Resource Type	Article
Subject	Cancer Research Genetics Oncology
Journal Impact Factor	5.3/2023
5-Year Journal Impact Factor	5/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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