多发性骨髓瘤（MM）是骨髓和骨髓外恶性浆细胞的一种癌症。我们之前为人类高风险MM特征化了一个VQ模型。各种VQ线呈现出不同的疾病表型和存活率，表明模型内部差异显著。在这里，我们使用全外显子测序和拷贝数变异（CNV）分析结合RNA-Seq来将VQ线分层成相应的簇：A组细胞具有单体染色体（chr）5和过度表达的基因和通路与人MM患者对硼替佐米（Btz）治疗敏感相关联。相反，B组VQ细胞携带chr3的反复扩增（Amp），展现出高风险MM的特征，包括Fam46c的下调，与功能性高风险MM相关的癌症生长通路的上调，以及Amp1q和高风险的UAMS-70和EMC-92基因签名的表达。一致地，与对Btz有短期反应的A组VQ细胞形成鲜明对比的是，B组VQ细胞在体内对Btz是新生的耐药性。我们的研究突出了B组VQ线作为高度代表人类MM亚型的超高风险。©2023。作者独家授权Springer Nature Limited。

Multiple myeloma (MM) is a cancer of malignant plasma cells in the bone marrow and extramedullary sites. We previously characterized a VQ model for human high-risk MM. The various VQ lines display different disease phenotypes and survival rates, suggesting significant intra-model variation. Here, we use whole-exome sequencing and copy number variation (CNV) analysis coupled with RNA-Seq to stratify the VQ lines into corresponding clusters: Group A cells had monosomy chromosome (chr) 5 and overexpressed genes and pathways associated with sensitivity to bortezomib (Btz) treatment in human MM patients. By contrast, Group B VQ cells carried recurrent amplification (Amp) of chr3 and displayed high-risk MM features, including downregulation of Fam46c, upregulation of cancer growth pathways associated with functional high-risk MM, and expression of Amp1q and high-risk UAMS-70 and EMC-92 gene signatures. Consistently, in sharp contrast to Group A VQ cells that showed short-term response to Btz, Group B VQ cells were de novo resistant to Btz in vivo. Our study highlights Group B VQ lines as highly representative of the human MM subset with ultrahigh risk.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.