A Novel BRD Family PROTAC Inhibitor dBET1 Exerts Great Anti-Cancer Effects by Targeting c-MYC in Acute Myeloid Leukemia Cells

Acute myeloid leukemia (AML) represents an aggressive hematopoietic malignancy with a prognosis inferior to that of other leukemias. Recent targeted therapies offer new opportunities to achieve better treatment outcomes. However, due to the complex heterogeneity of AML, its prognosis remains dismal....

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Kunlong, Gao, Li, Wang, Jianwei, Chu, Xinran, Zhang, Zimu, Zhang, Yongping, Fang, Fang, Tao, Yanfang, Li, Xiaolu, Tian, Yuanyuan, Li, Zhiheng, Sang, Xu, Ma, Li, Lu, Lihui, Chen, Yanling, Yu, Juanjuan, Zhuo, Ran, Wu, Shuiyan, Pan, Jian, Hu, Shaoyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Pathology and Oncology Archive
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272305/
https://www.ncbi.nlm.nih.gov/pubmed/35832114
http://dx.doi.org/10.3389/pore.2022.1610447
_version_ 1784744853132804096
author Zhang, Kunlong
Gao, Li
Wang, Jianwei
Chu, Xinran
Zhang, Zimu
Zhang, Yongping
Fang, Fang
Tao, Yanfang
Li, Xiaolu
Tian, Yuanyuan
Li, Zhiheng
Sang, Xu
Ma, Li
Lu, Lihui
Chen, Yanling
Yu, Juanjuan
Zhuo, Ran
Wu, Shuiyan
Pan, Jian
Hu, Shaoyan
author_facet Zhang, Kunlong
Gao, Li
Wang, Jianwei
Chu, Xinran
Zhang, Zimu
Zhang, Yongping
Fang, Fang
Tao, Yanfang
Li, Xiaolu
Tian, Yuanyuan
Li, Zhiheng
Sang, Xu
Ma, Li
Lu, Lihui
Chen, Yanling
Yu, Juanjuan
Zhuo, Ran
Wu, Shuiyan
Pan, Jian
Hu, Shaoyan
author_sort Zhang, Kunlong
collection PubMed
description Acute myeloid leukemia (AML) represents an aggressive hematopoietic malignancy with a prognosis inferior to that of other leukemias. Recent targeted therapies offer new opportunities to achieve better treatment outcomes. However, due to the complex heterogeneity of AML, its prognosis remains dismal. In this study, we first identified the correlation between high expression of BRD4 and overall survival of patients with AML. Targeted degradation of BRD2, BRD3, and BRD4 proteins by dBET1, a proteolysis-targeting chimera (PROTAC) against the bromodomain and extra-terminal domain (BET) family members, showed cytotoxic effects on Kasumi (AML1-ETO), NB4 (PML-RARa), THP-1 (MLL-AF9), and MV4-11 (MLL-AF4) AML cell lines representing different molecular subtypes of AML. Furthermore, we determined that dBET1 treatment arrested cell cycling and enhanced apoptosis and c-MYC was identified as the downstream target. Collectively, our results indicated that dBET1 had broad anti-cancer effects on AML cell lines with different molecular lesions and provided more benefits to patients with AML.
format Online
Article
Text
id pubmed-9272305
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-92723052022-07-12 A Novel BRD Family PROTAC Inhibitor dBET1 Exerts Great Anti-Cancer Effects by Targeting c-MYC in Acute Myeloid Leukemia Cells Zhang, Kunlong Gao, Li Wang, Jianwei Chu, Xinran Zhang, Zimu Zhang, Yongping Fang, Fang Tao, Yanfang Li, Xiaolu Tian, Yuanyuan Li, Zhiheng Sang, Xu Ma, Li Lu, Lihui Chen, Yanling Yu, Juanjuan Zhuo, Ran Wu, Shuiyan Pan, Jian Hu, Shaoyan Pathol Oncol Res Pathology and Oncology Archive Acute myeloid leukemia (AML) represents an aggressive hematopoietic malignancy with a prognosis inferior to that of other leukemias. Recent targeted therapies offer new opportunities to achieve better treatment outcomes. However, due to the complex heterogeneity of AML, its prognosis remains dismal. In this study, we first identified the correlation between high expression of BRD4 and overall survival of patients with AML. Targeted degradation of BRD2, BRD3, and BRD4 proteins by dBET1, a proteolysis-targeting chimera (PROTAC) against the bromodomain and extra-terminal domain (BET) family members, showed cytotoxic effects on Kasumi (AML1-ETO), NB4 (PML-RARa), THP-1 (MLL-AF9), and MV4-11 (MLL-AF4) AML cell lines representing different molecular subtypes of AML. Furthermore, we determined that dBET1 treatment arrested cell cycling and enhanced apoptosis and c-MYC was identified as the downstream target. Collectively, our results indicated that dBET1 had broad anti-cancer effects on AML cell lines with different molecular lesions and provided more benefits to patients with AML. Frontiers Media S.A. 2022-06-27 /pmc/articles/PMC9272305/ /pubmed/35832114 http://dx.doi.org/10.3389/pore.2022.1610447 Text en Copyright © 2022 Zhang, Gao, Wang, Chu, Zhang, Zhang, Fang, Tao, Li, Tian, Li, Sang, Ma, Lu, Chen, Yu, Zhuo, Wu, Pan and Hu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pathology and Oncology Archive
Zhang, Kunlong
Gao, Li
Wang, Jianwei
Chu, Xinran
Zhang, Zimu
Zhang, Yongping
Fang, Fang
Tao, Yanfang
Li, Xiaolu
Tian, Yuanyuan
Li, Zhiheng
Sang, Xu
Ma, Li
Lu, Lihui
Chen, Yanling
Yu, Juanjuan
Zhuo, Ran
Wu, Shuiyan
Pan, Jian
Hu, Shaoyan
A Novel BRD Family PROTAC Inhibitor dBET1 Exerts Great Anti-Cancer Effects by Targeting c-MYC in Acute Myeloid Leukemia Cells
title A Novel BRD Family PROTAC Inhibitor dBET1 Exerts Great Anti-Cancer Effects by Targeting c-MYC in Acute Myeloid Leukemia Cells
title_full A Novel BRD Family PROTAC Inhibitor dBET1 Exerts Great Anti-Cancer Effects by Targeting c-MYC in Acute Myeloid Leukemia Cells
title_fullStr A Novel BRD Family PROTAC Inhibitor dBET1 Exerts Great Anti-Cancer Effects by Targeting c-MYC in Acute Myeloid Leukemia Cells
title_full_unstemmed A Novel BRD Family PROTAC Inhibitor dBET1 Exerts Great Anti-Cancer Effects by Targeting c-MYC in Acute Myeloid Leukemia Cells
title_short A Novel BRD Family PROTAC Inhibitor dBET1 Exerts Great Anti-Cancer Effects by Targeting c-MYC in Acute Myeloid Leukemia Cells
title_sort novel brd family protac inhibitor dbet1 exerts great anti-cancer effects by targeting c-myc in acute myeloid leukemia cells
topic Pathology and Oncology Archive
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9272305/
https://www.ncbi.nlm.nih.gov/pubmed/35832114
http://dx.doi.org/10.3389/pore.2022.1610447
work_keys_str_mv AT zhangkunlong anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT gaoli anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT wangjianwei anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT chuxinran anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT zhangzimu anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT zhangyongping anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT fangfang anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT taoyanfang anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT lixiaolu anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT tianyuanyuan anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT lizhiheng anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT sangxu anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT mali anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT lulihui anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT chenyanling anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT yujuanjuan anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT zhuoran anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT wushuiyan anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT panjian anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT hushaoyan anovelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT zhangkunlong novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT gaoli novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT wangjianwei novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT chuxinran novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT zhangzimu novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT zhangyongping novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT fangfang novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT taoyanfang novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT lixiaolu novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT tianyuanyuan novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT lizhiheng novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT sangxu novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT mali novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT lulihui novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT chenyanling novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT yujuanjuan novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT zhuoran novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT wushuiyan novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT panjian novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells
AT hushaoyan novelbrdfamilyprotacinhibitordbet1exertsgreatanticancereffectsbytargetingcmycinacutemyeloidleukemiacells

Ejemplares similares