Immunoglobulin M (IgM) multiple myeloma (MM) is a rare disease subgroup. Its differentiation from other IgM-producing gammopathies such as Waldenström macroglobulinemia (WM) has not been well characterized but is essential for proper risk assessment and treatment. In this study, we investigated genomic and transcriptomic characteristics of IgM-MM samples using whole-genome and transcriptome sequencing to identify differentiating characteristics from non-IgM-MM and WM. Our results suggest that IgM-MM shares most of its defining structural variants and gene-expression profiling with MM, but has some key characteristics, including t(11;14) translocation, chromosome 6 and 13 deletion as well as distinct molecular and transcription-factor signatures. Furthermore, IgM-MM translocations were predominantly characterized by VHDHJH recombination-induced breakpoints, as opposed to the usual class-switching region breakpoints; coupled with its lack of class switching, these data favor a pre-germinal center origin. Finally, we found elevated expression of clinically relevant targets, including CD20 and Bruton tyrosine kinase, as well as high BCL2/BCL2L1 ratio in IgM-MM, providing potential for targeted therapeutics.

中文翻译：

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IgM-MM 主要是一种前生发中心疾病，具有与 WM 不同的基因组和转录组特征。

免疫球蛋白 M (IgM) 多发性骨髓瘤 (MM) 是一种罕见的疾病亚组。它与其他产生 IgM 的丙种球蛋白病（如华氏巨球蛋白血症 (WM)）的区别尚未得到很好的表征，但对于正确的风险评估和治疗至关重要。在这项研究中，我们使用全基因组和转录组测序研究了 IgM-MM 样本的基因组和转录组学特征，以确定与非 IgM-MM 和 WM 的区别特征。我们的结果表明，IgM-MM 与 MM 共享其大部分定义结构变异和基因表达谱，但具有一些关键特征，包括 t(11;14) 易位、6 号和 13 号染色体缺失以及独特的分子和转录-因子签名。此外，IgM-MM 易位的主要特征是 VHDHJH 重组诱导的断点，而不是通常的类别转换区域断点；加上其缺乏类别转换，这些数据有利于前生发中心起源。最后，我们发现临床相关靶标的表达升高，包括 CD20 和布鲁顿酪氨酸激酶，以及 IgM-MM 中的高 BCL2/BCL2L1 比率，为靶向治疗提供了潜力。