Alzrigat, Mohammad

Heckman, Caroline A.

Jernberg-Wiklund, Helena

Jin,  Jian

Kalushkova,  Antonia

Ma,  Anqi

Majumder, Muntasir Mamun

Nahi, Hareth

Nilsson, Kenneth

Párraga,  Alba Atienza

Öberg,  Fredrik

Österborg,  Anders

English

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

Párraga, Alba Atienza

Majumder, Muntasir

Ma, Anqi

Jin, Jian

Heckman, Caroline

Öberg, Fredrik

Kalushkova, Antonia

Jernberg Wiklund, Helena

Publikationer från Uppsala Universitet

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 bromodomain

Helsingin yliopiston digitaalinen arkisto

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

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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Publikationer från Uppsala Universitet

Helsingin yliopiston digitaalinen arkisto

Digitala Vetenskapliga Arkivet - Academic Archive On-line

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