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.

Mohammad Alzrigat,Jian Jin,Muntasir Mamun Majumder,Hareth Nahi,Kenneth Nilsson,Anders Österborg,Alba Atienza Párraga,Antonia Kalushkova,Caroline A Heckman,Fredrik Öberg,Helena Jernberg-Wiklund,Anqi Ma

doi:10.18632/oncotarget.21909

Abstract

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.

Highlights

Multiple myeloma (MM) is a genetically complex and heterogeneous disease characterized by abnormal proliferation of clonal plasmablasts/plasma cells (PCs) in the bone marrow (BM) [1,2,3]
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 B Lymphoma MoMLV Insertion Region 1 (BMI-1) protein and the associated repressive histone mark H2AK119ub, leaving other polycomb repressive complex 1 (PRC1) subunits such as CBX-7 and the catalytic subunit RING1B unaffected
By reverse transcription quantitative real-time PCR (RT-qPCR) we found that PTC-209 treatment did not reduce the expression of BMI-1 at the mRNA levels, but rather led to an increase in BMI-1 transcript levels in most of the MM cell lines tested in this study (Figure 2A)

Summary

Introduction

Multiple myeloma (MM) is a genetically complex and heterogeneous disease characterized by abnormal proliferation of clonal plasmablasts/plasma cells (PCs) in the bone marrow (BM) [1,2,3]. Deregulated expression and function of epigenetic modifiers such as the enhancer of zeste homolog 2 (EZH2) [16,17,18], the multiple myeloma SET domain containing-protein (MMSET) [19, 20] and members of the Jumonji C-domain-containing histone demethylases KDM6B [21] and KDM3A [22] are frequently observed in MM. These data point towards a potential role of epigenetic reprogramming in MM, and highlight epigenetic modifiers as promising therapeutic targets in MM

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Results

Conclusion