Da Vià Matteo Claudio, Lazzaroni Francesca, Matera Antonio, Marella Alessio, Maeda Akihiro, De Magistris Claudio, Pettine Loredana, Solimando Antonio Giovanni, Desantis Vanessa, Peretti Giuseppe M, Mangiavini Laura, Giorgino Riccardo, Fabris Sonia, Pioggia Stefania, Marchetti Alfredo, Barbieri Marzia, Lonati Silvia, Cattaneo Alessandra, Tornese Marta, Scopetti Margherita, Calvi Emanuele, Latifinavid Nayyer, Castellano Giancarlo, Torricelli Federica, Neri Antonino, Fokkema Cathelijne, Cupedo Tom, Lionetti Marta, Passamonti Francesco, Bolli Niccolò
Hematology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
Blood. 2025 Jun 26;145(26):3124-3138. doi: 10.1182/blood.2024025643.
Multiple myeloma (MM) is driven by clonal plasma cell (cPC)-intrinsic factors and changes in the tumor microenvironment (TME). To investigate whether residual polyclonal PCs (pPCs) are disrupted, single-cell (sc) RNA sequencing (scRNA-seq) and sc B-cell receptor analysis were applied in a cohort of 46 samples with PC dyscrasias and 21 healthy donors (HDs). Of 234 789 PCs, 64 432 were genotypically identified as pPCs with frequencies decreasing over different disease stages, from 23.66% in monoclonal gammopathy of undetermined significance to 3.23% in MMs (P = .00012). Both cPCs and pPCs had a comparable expression of typical lineage markers (ie, CD38 and CD138), whereas others were more variable (CD27 and ITGB7). Only cPCs overexpressed oncogenes (eg, CCND1/2 and NSD2), but CCND3 was often expressed in pPCs. B-cell maturation antigen was expressed on both pPCs and cPCs, whereas GPRC5D was mostly upregulated in cPCs with implications for on-target, off-tumor activity of targeted immunotherapies. In comparison with HDs, pPCs from patients showed upregulated autophagy and disrupted interaction with TME. Importantly, interferon-related pathways were significantly enriched in pPCs from patients vs HDs (adjusted P < .05) showing an inflamed phenotype affecting genotypically normal PCs. The function of pPCs was consequently affected and correlated with immunoparesis, driven by disrupted cellular interactions with TME. Leveraging our scRNA-seq data, we derived a "healthy PC signature" that could be applied to bulk transcriptomics from the CoMMpass data set and predicted significantly better progression-free survival and overall survival (log-rank P < .05 for both). Our findings show that genotypic sc identification of pPCs in PC dyscrasias has relevant pathogenic and clinical implications.
多发性骨髓瘤（MM）由克隆性浆细胞（cPC）内在因素和肿瘤微环境（TME）变化驱动。为了研究残留多克隆浆细胞（pPC）是否受到破坏，对46例浆细胞发育异常患者样本和21例健康供体（HD）进行了单细胞（sc）RNA测序（scRNA-seq）和sc B细胞受体分析。在234789个浆细胞中，64432个在基因分型上被鉴定为pPC，其频率在不同疾病阶段逐渐降低，从不明意义的单克隆丙种球蛋白病中的23.66%降至MM中的3.23%（P = 0.00012）。cPC和pPC均有类似的典型谱系标志物（即CD38和CD138）表达，而其他标志物的表达更具变异性（CD27和ITGB7）。只有cPC过表达癌基因（如CCND1/2和NSD2），但CCND3常在pPC中表达。B细胞成熟抗原在pPC和cPC上均有表达，而GPRC5D大多在cPC中上调，这对靶向免疫治疗的肿瘤外靶向活性有影响。与HD相比，患者的pPC显示出自噬上调以及与TME的相互作用受到破坏。重要的是，与HD相比，患者pPC中干扰素相关通路显著富集（校正P < 0.05），显示出影响基因分型正常浆细胞的炎症表型。pPC的功能因此受到影响，并与免疫不全相关，这是由与TME的细胞相互作用破坏所驱动的。利用我们的scRNA-seq数据，我们得出了一个“健康浆细胞特征”，可应用于来自CoMMpass数据集的批量转录组学，并预测无进展生存期和总生存期显著更好（两者的对数秩P < 0.05）。我们的研究结果表明，在浆细胞发育异常中对pPC进行基因分型的sc鉴定具有相关的致病和临床意义。
