Abstract
Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MCL) with durable responses seen in 30%-50% of patients. Given that a large proportion of patients will not respond, BZM resistance is a significant barrier to use this agent in MCL. We hypothesized that a subset of aberrantly methylated genes may be modulating BZM response in MCL patients. Genome-wide DNA methylation analysis using a NimbleGen array platform revealed a striking promoter hypomethylation in MCL patient samples following BZM treatment. Pathway analysis of differentially methylated genes identified molecular mechanisms of cancer as a top canonical pathway enriched among hypomethylated genes in BZM treated samples. Noxa, a pro-apoptotic Bcl-2 family member essential for the cytotoxicity of BZM, was significantly hypomethylated and induced following BZM treatment. Therapeutically, we could demethylate Noxa and induce anti-lymphoma activity using BZM and the DNA methytransferase inhibitor Decitabine (DAC) and their combination in vitro and in vivo in BZM resistant MCL cells. These findings suggest a role for dynamic Noxa methylation for the therapeutic benefit of BZM. Potent and synergistic cytotoxicity between BZM and DAC in vitro and in vivo supports a strategy for using epigenetic priming to overcome BZM resistance in relapsed MCL patients.
Highlights
Mantle Cell Lymphoma (MCL) is an aggressive and mostly incurable B cell malignancy with frequent relapses after initial response to standard chemotherapy
Genomic DNA was extracted from tumor cells purified from the peripheral blood of 6 newly diagnosed MCL patients treated with singleagent BZM at the National Institutes of Health
The present data show the induction of genome-wide hypomethylation in MCL patient samples following BZM treatment, suggesting that the BZM induced epigenetic changes may contribute to its cytotoxic mechanism in MCL
Summary
Mantle Cell Lymphoma (MCL) is an aggressive and mostly incurable B cell malignancy with frequent relapses after initial response to standard chemotherapy. Bortezomib (BZM) is the first proteasome inhibitor approved by the FDA for relapsed and refractory MCL, with durable responses in 30%–50% of MCL patients in phase II studies [1, 2]. BZM is a highly selective, reversible inhibitor of 26S proteasome leading to the modulation of several biological processes, such as cell cycle arrest, induction of apoptosis, deregulation of NFκB activity, and induction of endoplasmic reticular (ER) stress. Our group and others have identified aberrantly methylated genes in MCL controlling critical cellular processes like cell cycle, transcription and regulation of gene expression [3]. We hypothesized that a subset of aberrantly methylated genes may be contributing to the response to BZM treatment by inducing DNA hypomethylation and cellular reprogramming leading to a significant antitumor activity
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