Aberrant single-cell phenotype and clinical implications of genotypically defined polyclonal plasma cells in myeloma.

IF 21 1区 医学 Q1 HEMATOLOGY
Blood Pub Date : 2025-06-26 DOI:10.1182/blood.2024025643
Matteo Claudio Da Vià, Francesca Lazzaroni, Antonio Matera, Alessio Marella, Akihiro Maeda, Claudio De Magistris, Loredana Pettine, Antonio Giovanni Solimando, Vanessa Desantis, Giuseppe M Peretti, Laura Mangiavini, Riccardo Giorgino, Sonia Fabris, Stefania Pioggia, Alfredo Marchetti, Marzia Barbieri, Silvia Lonati, Alessandra Cattaneo, Marta Tornese, Margherita Scopetti, Emanuele Calvi, Nayyer Latifinavid, Giancarlo Castellano, Federica Torricelli, Antonino Neri, Cathelijne Fokkema, Tom Cupedo, Marta Lionetti, Francesco Passamonti, Niccolò Bolli
{"title":"Aberrant single-cell phenotype and clinical implications of genotypically defined polyclonal plasma cells in myeloma.","authors":"Matteo Claudio Da Vià, Francesca Lazzaroni, Antonio Matera, Alessio Marella, Akihiro Maeda, Claudio De Magistris, Loredana Pettine, Antonio Giovanni Solimando, Vanessa Desantis, Giuseppe M Peretti, Laura Mangiavini, Riccardo Giorgino, Sonia Fabris, Stefania Pioggia, Alfredo Marchetti, Marzia Barbieri, Silvia Lonati, Alessandra Cattaneo, Marta Tornese, Margherita Scopetti, Emanuele Calvi, Nayyer Latifinavid, Giancarlo Castellano, Federica Torricelli, Antonino Neri, Cathelijne Fokkema, Tom Cupedo, Marta Lionetti, Francesco Passamonti, Niccolò Bolli","doi":"10.1182/blood.2024025643","DOIUrl":null,"url":null,"abstract":"<p><strong>Abstract: </strong>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.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"3124-3138"},"PeriodicalIF":21.0000,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1182/blood.2024025643","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Abstract: 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.

骨髓瘤中基因典型定义的多克隆浆细胞的异常单细胞表型和临床意义。
多发性骨髓瘤是由克隆浆细胞(cPC)内在因子和致瘤微环境(TME)变化驱动的。为了研究残余的多克隆PC (pPCs)是否被破坏,我们对46例PC dysdysasia患者和21例健康供者(hd)进行了单细胞(sc) RNAseq和sc b细胞受体分析。在n=234,789例pc中,64,432例被基因典型地鉴定为pPCs,其频率在不同的疾病阶段呈下降趋势,从未确定意义的单克隆γ病(MGUS)的23.66%到mm的3.23% (p=0.00012)。cpc和pPCs的典型谱系标记(即CD38, CD138)的表达相似,而其他谱系标记(CD27, ITGB7)则变化较大。只有cpc过表达癌基因(如CCND1/2, NSD2),但CCND3经常在pPCs中表达。BCMA在p-和cPCs上均有表达,而GPRC5D在cPCs中大多表达上调,这与靶向免疫治疗的靶向、非肿瘤活性有关。与HDs相比,患者的pPCs表现出自噬上调和与TME相互作用的破坏。重要的是,干扰素相关通路在患者与hd的pPCs中显著富集(p校正< 0.05),显示炎症表型影响基因典型正常的pc。pPCs的功能因此受到影响,并与免疫轻瘫相关,这是由细胞与TME相互作用的破坏所驱动的。利用我们的scRNAseq数据,我们得出了一个“健康的PC签名”,可以应用于来自CoMMpass数据集的大量转录组学,并显著预测更好的PFS和OS(两者的log rank p < 0.05)。我们的研究结果表明,基因型、单细胞鉴定pccs在PC dysdysia中具有相关的致病和临床意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Blood
Blood 医学-血液学
CiteScore
23.60
自引率
3.90%
发文量
955
审稿时长
1 months
期刊介绍: Blood, the official journal of the American Society of Hematology, published online and in print, provides an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. Primary research articles will be published under the following scientific categories: Clinical Trials and Observations; Gene Therapy; Hematopoiesis and Stem Cells; Immunobiology and Immunotherapy scope; Myeloid Neoplasia; Lymphoid Neoplasia; Phagocytes, Granulocytes and Myelopoiesis; Platelets and Thrombopoiesis; Red Cells, Iron and Erythropoiesis; Thrombosis and Hemostasis; Transfusion Medicine; Transplantation; and Vascular Biology. Papers can be listed under more than one category as appropriate.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信