作者
Sujan Piya, Hong Mu, Seemana Bhattacharya, Philip L Lorenzi, R Eric Davis, Teresa McQueen, Vivian Ruvolo, Natalia Baran, Zhiqiang Wang, Yimin Qian, Craig M Crews, Marina Konopleva, Jo Ishizawa, M James You, Hagop Kantarjian, Michael Andreeff, Gautam Borthakur
发表日期
2019/5/1
期刊
The Journal of clinical investigation
卷号
129
期号
5
页码范围
1878-1894
出版商
American Society for Clinical Investigation
简介
The antileukemic effect of inhibiting bromodomain and extra-terminal domain-containing (BET-containing) proteins (BETPs) such as BRD4 has largely been largely attributed to transcriptional downregulation of cellular anabolic and antiapoptotic processes, but its effect on the bone marrow microenvironment, a sanctuary favoring the persistence of leukemic stem/progenitor cells, is unexplored. Sustained degradation of BETP with the small-molecule BET proteolysis-targeting chimera (PROTAC) ARV-825 resulted in a marked downregulation of surface CXCR4 and CD44, key proteins in leukemia-microenvironment interactions, in acute myeloid leukemia (AML) cells. Abrogation of surface CXCR4 expression impaired SDF-1α–directed migration and was mediated through transcriptional downregulation of PIM1 kinase, which in turn phosphorylates CXCR4 and facilitates its surface localization. Downregulation of …
学术搜索中的文章
S Piya, H Mu, S Bhattacharya, PL Lorenzi, RE Davis… - The Journal of clinical investigation, 2019