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- W4224298045 endingPage "106841" @default.
- W4224298045 startingPage "106841" @default.
- W4224298045 abstract "Waldenström macroglobulinemia (WM) is a B cell lymphoma characterized by the overproduction of a monoclonal IgM antibody, a leading pathogenic feature of the disease. Current therapies are based on our knowledge at the signaling and genetic scale, but recent research has identified epigenetic dysregulation as one of the important dynamics in the biology of this disease. In this study, we found that Mixed-lineage leukemia 1 (MLL1) histone methyltransferase and its chromatin tethering partner Menin are upregulated in WM patients. KMT2A knockdown using short hairpin RNA (shRNA) and inhibition of MLL1 function using the menin-MLL1 inhibitor (MI-2) in WM cells resulted in a significant reduction in IgM levels without significantly impacting WM cell growth and survival. Further analysis identified MLL1 binding at multiple sites in the 5' Eμ enhancer of the immunoglobulin heavy (IGH) chain. We found increased histone 3 lysine 4 trimethylation (H3K4me3) enrichment at multiple MLL1 binding sites upon LPS stimulation, a known inducer of IgM. Finally, we found that disruption of Menin-MLL1 complex using the MI-2 inhibitor in tumor-bearing mice significantly reduced human IgM levels in mice sera. Taken together, these results identify MLL1 as a regulator of IgM and define MLL1 as a new therapeutic target for WM." @default.
- W4224298045 created "2022-04-26" @default.
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- W4224298045 date "2022-05-01" @default.
- W4224298045 modified "2023-09-26" @default.
- W4224298045 title "MLL1 inhibition reduces IgM levels in Waldenström macroglobulinemia" @default.
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- W4224298045 doi "https://doi.org/10.1016/j.leukres.2022.106841" @default.
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