Epigenetic alterations play an important role in the pathogenesis in multiple myeloma, but their biological and clinical relevance is not fully understood. Here, we show that DOT1L, which catalyzes methylation of histone H3 lysine 79, is required for myeloma cell survival. DOT1L expression levels were higher in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma than in normal plasma cells. Treatment with a DOT1L inhibitor induced cell cycle arrest and apoptosis in myeloma cells, and strongly suppressed cell proliferation in vitro. The anti-myeloma effect of DOT1L inhibition was confirmed in a mouse xenograft model. Chromatin immunoprecipitation-sequencing and microarray analysis revealed that DOT1L inhibition downregulated histone H3 lysine 79 dimethylation and expression of IRF4-MYC signaling genes in myeloma cells. In addition, DOT1L inhibition upregulated genes associated with immune responses and interferon signaling. Myeloma cells with histone modifier mutations or lower IRF4/MYC expression were less sensitive to DOT1L inhibition, but with prolonged treatment anti-proliferative effects were achieved in these cells. Our data suggest that DOT1L plays an essential role in the development of multiple myeloma and that DOT1L inhibition may provide new therapies for myeloma treatment.

Hypertension within 2 weeks of initiation of therapy may be a predictor of the anti-cancer efficacy of sorafenib when used for the treatment of advanced hepatocellular carcinoma.

No abstract

A 74-year-old Japanese woman was diagnosed with rheumatoid arthritis due to polyarthralgia. She was prescribed various disease-modifying anti-rheumatic drugs, but most of them were discontinued because of side effects or poor effectiveness. She was referred to our hospital in 2004, and etanercept was administered from June 2005. This resulted in rapid improvement of polyarthritis; however, she developed disorientation from February 2006. She was admitted to our hospital because of convulsions and loss of consciousness. She was diagnosed with progressive multifocal leukoencephalopathy on the basis of clinical symptoms and magnetic resonance imaging of the brain. In this significant and important case, leukoencephalopathy occurred during etanercept administration, and we refer to the risk of anti-TNFalpha drugs.

A 74-year-old Japanese woman was diagnosed with rheumatoid arthritis due to polyarthralgia. She was prescribed various disease-modifying anti-rheumatic drugs, but most of them were discontinued because of side effects or poor effectiveness. She was referred to our hospital in 2004, and etanercept was administered from June 2005. This resulted in rapid improvement of polyarthritis; however, she developed disorientation from February 2006. She was admitted to our hospital because of convulsions and loss of consciousness. She was diagnosed with progressive multifocal leukoencephalopathy on the basis of clinical symptoms and magnetic resonance imaging of the brain. In this significant and important case, leukoencephalopathy occurred during etanercept administration, and we refer to the risk of anti-TNFalpha drugs.