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J Clin Invest. 2019 Feb 21;129(5):1878-1894. doi: 10.1172/JCI120654. Print 2019 May 1.

BETP degradation simultaneously targets acute myelogenous leukemia stem cells and the microenvironment.

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Section of Molecular Hematology and Therapy.
Department of Leukemia.
Department of Bioinformatics and Computational Biology, and.
Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Arvinas Inc., New Haven, Connecticut, USA.
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut, USA.
Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.


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.


Cancer; Cell Biology; Epigenetics; Oncology

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