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- Title
BETP degradation simultaneously targets acute myelogenous leukemia stem cells and the microenvironment.
- Authors
Piya, Sujan; Hong Mu; Bhattacharya, Seemana; Lorenzi, Philip L.; Davis, R. Eric; McQueen, Teresa; Ruvolo, Vivian; Baran, Natalia; Zhiqiang Wang; Yimin Qian; Crews, Craig M.; Konopleva, Marina; Jo Ishizawa; You, M. James; Hagop Kantarjian; Andreeff, Michael; Borthakur, Gautam; Mu, Hong; Wang, Zhiqiang; Qian, Yimin
- Abstract
Anti-leukemic effect of BET/BRD4 (BETP) protein inhibition has been largely attributed to transcriptional downregulation of cellular anabolic/anti-apoptotic processes but its effect on bone marrow microenvironment, a sanctuary favoring persistence of leukemia stem/progenitor cells, is unexplored. Sustained degradation of BETP with small-molecule BET proteolysis-targeting chimera (PROTAC), ARV-825, resulted in marked downregulation of surface CXCR4 and CD44, key proteins in leukemia-microenvironment interaction, in AML cells. Abrogation of surface CXCR4 expression impaired SDF-1α directed migration and was mediated through transcriptional down-regulation of PIM1 kinase that in turn phosphorylates CXCR4 and facilitates its surface localization. Down-regulation of CD44/CD44v8-10 impaired cystine uptake, lowered intracellular reduced glutathione and increased oxidative stress. More importantly, BETP degradation markedly decreased CD34+CD38-CD90-CD45RA+ leukemic stem cell population and alone or in combination with Cytarabine, prolonged survival in mouse model of human leukemia including AML-PDX. Gene expression profiling and single cell proteomics confirmed down regulation of the gene signatures associated with 'stemness' in AML and Wnt/β-catenin, Myc pathways. Hence, BETP degradation by ARV-825 simultaneously targets cell intrinsic signaling, stromal interactions and metabolism in AML.
- Subjects
STEM cells; GENE expression profiling; ACUTE myeloid leukemia; CYTARABINE; CELL populations; PROGENITOR cells
- Publication
Journal of Clinical Investigation, 2019, Vol 129, Issue 5, p1878
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI120654