Karbalivand Mona, Almada Luciana L, Ansell Stephen M, Fernandez-Zapico Martin E, Elsawa Sherine F
University of New Hampshire, Department of Molecular, Cellular and Biomedical Sciences, Durham, NH 03824, USA.
Schultz Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
Leuk Res. 2022 May;116:106841. doi: 10.1016/j.leukres.2022.106841. Epub 2022 Apr 19.
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.
华氏巨球蛋白血症（WM）是一种B细胞淋巴瘤，其特征是单克隆IgM抗体过度产生，这是该疾病的主要致病特征。目前的治疗方法基于我们在信号传导和基因层面的认知，但最近的研究已将表观遗传失调确定为该疾病生物学中的重要动态之一。在本研究中，我们发现混合谱系白血病1（MLL1）组蛋白甲基转移酶及其染色质结合伴侣Menin在WM患者中上调。在WM细胞中使用短发夹RNA（shRNA）敲低KMT2A以及使用Menin-MLL1抑制剂（MI-2）抑制MLL1功能，导致IgM水平显著降低，而对WM细胞的生长和存活没有显著影响。进一步分析确定MLL1在免疫球蛋白重链（IGH）的5'Eμ增强子中的多个位点结合。我们发现，在已知的IgM诱导剂脂多糖（LPS）刺激后，多个MLL1结合位点处的组蛋白3赖氨酸4三甲基化（H3K4me3）富集增加。最后，我们发现在荷瘤小鼠中使用MI-2抑制剂破坏Menin-MLL1复合物可显著降低小鼠血清中的人IgM水平。综上所述，这些结果确定MLL1为IgM的调节因子，并将MLL1定义为WM的新治疗靶点。
