The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomains
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Mohammad Alzrigat1, Alba Atienza Párraga1, Muntasir Mamun Majumder2, Anqi Ma3, Jian Jin3, Anders Österborg4, Hareth Nahi5, Kenneth Nilsson1, Caroline A. Heckman2, Fredrik Öberg1, Antonia Kalushkova1 and Helena Jernberg-Wiklund1
1Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
2Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
3Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
4Department of Oncology-Pathology, Karolinska University Hospital, Solna, Stockholm, Sweden
5Department of Medicine, Unit of Hematology, Karolinska University Hospital, Huddinge, Stockholm, Sweden
Helena Jernberg-Wiklund, email: [email protected]
Mohammad Alzrigat, email: [email protected]
Keywords: multiple myeloma, epigenetics, polycomb, BMI-1, PTC-209
Received: February 14, 2017 Accepted: October 10, 2017 Published: October 20, 2017
Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.
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