title: Harnessing Noxa demethylation to overcome Bortezomib resistance in mantle cell lymphoma.
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.
authors.affiliation: Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Violetta V
authors.initials: VV
authors.lastname: Leshchenko
authors.affiliation: Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Kuo
authors.affiliation: Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Zewei
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Weniger
authors.affiliation: Department of Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Overbey
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Kieron
authors.initials: K
authors.lastname: Dunleavy
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
authors.affiliation: Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Parekh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000737:chemistry; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D019175:DNA Methylation; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D061988:Proteasome Inhibitors / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012008:Recurrence
chemical_list: D000970:Antineoplastic Agents; C498702:PMAIP1 protein, human; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D000069286:Bortezomib; D000077209:Decitabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine
keywords: Bortezomib; Noxa; mantle cell lymphoma; methylation; resistance