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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.

Author information

1
Section of Molecular Hematology and Therapy.
2
Department of Leukemia.
3
Department of Bioinformatics and Computational Biology, and.
4
Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
5
Arvinas Inc., New Haven, Connecticut, USA.
6
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut, USA.
7
Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

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.

KEYWORDS:

Cancer; Cell Biology; Epigenetics; Oncology

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