Harnessing Noxa demethylation to overcome Bortezomib resistance in mantle cell lymphoma
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Violetta V. Leshchenko1, Pei-Yu Kuo1, Zewei Jiang1, Marc A. Weniger2, Jessica Overbey3, Kieron Dunleavy4, Wyndham H. Wilson4, Adrian Wiestner2, Samir Parekh1
1Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
3Department of Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
4Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Samir Parekh, e-mail: firstname.lastname@example.org
Keywords: Mantle cell lymphoma, Noxa, methylation, Bortezomib, Resistance
Received: September 19, 2014 Accepted: December 13, 2014 Published: February 25, 2015
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.
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