Project description:Bortezomib (BZM) is the first proteasome inhibitor approved for relapsed Mantle Cell Lymphoma (MCL) with durable responses seen in 30%-50% of patients. The biological basis for differences in response to BZM is not completely understood. Our previous work demonstrated marked differences in methylation between primary MCL and normal B cells. We hypothesized that a subset of aberrantly methylated genes may be modulating BZM response in MCL patients. We examined genome-wide DNA methylation profiles in MCL patient treated with BZM using a NimbleGen array platform. DNA methylation analysis 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. Noxa depletion by RNA interference protected MCL cells from death by these agents. These findings suggest a role for dynamic Noxa methylation for 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. Our data demonstrate that genomic methylation profiling can provide mechanistic insights to guide novel therapeutic approaches.

2017-02-09 | GSE58165 | GEO

Tonsil cell atlas Data Access Commitee

Project description:Data Access Committee EGAC00001002807

| EGAC00001002807 | EGA