AbstractMultiple myeloma (MM) is a heterogeneous and incurable tumor characterized by the malignant proliferation of plasma cells. It is necessary to clarify the heterogeneity of MM and identify new theranostic targets. We constructed a single-cell transcriptome profile of 48,293 bone marrow cells from MM patients and health donors (HDs) annotated with 7 continuous B lymphocyte lineages.

摘要多发性骨髓瘤（MM）是一种异质性且不可治愈的肿瘤，其特征是浆细胞的恶性增殖。有必要澄清MM的异质性并确定新的治疗诊断目标。。

Through CellChat, we discovered that the communication among B lymphocyte lineages between MM and HDs was disrupted, and unique signaling molecules were observed. Through pseudotime analysis, it was found that the differences between MM and HDs were mainly reflected in plasma cells. These differences are primarily related to various biological processes involving mitochondria.

通过CellChat，我们发现MM和HDs之间B淋巴细胞谱系之间的通讯被破坏，并观察到独特的信号分子。通过伪时间分析，发现MM和HDs之间的差异主要反映在浆细胞中。这些差异主要与涉及线粒体的各种生物过程有关。

Then, we identified the key subpopulation associated with the malignant proliferation of plasma cells. This group of cells exhibited strong proliferation ability, high CNV scores, high expression of frequently mutated genes, and strong glucose metabolic activity. Furthermore, we demonstrated the therapeutic potential of WNK1 as a target.

然后，我们确定了与浆细胞恶性增殖相关的关键亚群。这组细胞表现出强大的增殖能力，高CNV评分，频繁突变基因的高表达以及强大的葡萄糖代谢活性。此外，我们证明了WNK1作为靶标的治疗潜力。

Our study provides new insights into the development of B cells and the heterogeneity of plasma cells in MM and suggests that WNK1 is a potential therapeutic target for MM..

我们的研究为MM中B细胞的发育和浆细胞的异质性提供了新的见解，并表明WNK1是MM的潜在治疗靶点。。

IntroductionMultiple myeloma (MM) is a prevalent clinical malignant tumor that originates from the malignant proliferation of plasma cells derived from B lymphocytes and has the second-highest incidence rate among hematological tumors in European and American countries [1]. In the United States, there are approximately 35,000 cases of new diagnosis MM (NDMM) each year, with over 12,000 patients dying from MM [2].

。在美国，每年约有35000例新诊断MM（NDMM），超过12000例患者死于MM（2）。

With the emergence of treatment methods such as proteasome inhibitors, immunotherapy, CAR-T cells, autologous hematopoietic stem cell transplantation, and bispecific antibodies, the management of MM has significantly improved [3]. In addition, more than 50% of patients have a 5-year overall survival period [4].

随着蛋白酶体抑制剂、免疫疗法、CAR-T细胞、自体造血干细胞移植和双特异性抗体等治疗方法的出现，MM的治疗得到了显著改善。此外，超过50%的患者有5年的总生存期（4）。

However, MM is still a disease that is difficult to cure at this stage. Therefore, clarifying the pathogenesis of MM and identifying new theranostic targets remain the top priorities in current MM research [5].Single-cell RNA sequencing (scRNA-seq) technology is a revolutionary technique that allows scientists to better understand the differences between tumors and the microenvironment [6].

。因此，阐明MM的发病机制并确定新的治疗诊断靶点仍然是当前MM研究的首要任务〔5〕。单细胞RNA测序（scRNA-seq）技术是一种革命性的技术，它使科学家能够更好地了解肿瘤与微环境之间的差异。

Currently, it has been applied in various blood cancers, including leukemia [7, 8], multiple myeloma [9, 10], myelodysplastic syndrome [11], and other highly heterogeneous diseases [12, 13]. Numerous studies have used scRNA-seq to investigate MM. Ling et al. conducted scRNA-seq on bone marrow samples from 9 MM at various Revised International Staging System (R-ISS) stages.

目前，它已被应用于各种血液癌症，包括白血病[7，8]，多发性骨髓瘤[9，10]，骨髓增生异常综合征[11]和其他高度异质性疾病[12，13]。许多研究已经使用scRNA-seq来研究MM。Ling等人在各种修订的国际分期系统（R-ISS）阶段对9 MM的骨髓样本进行了scRNA-seq。

They discovered novel molecules (PDIA6, LETM1), networks (UQCRB-PDIA6, STAT1-LETM1), and crosstalk pairs (CCL3/CCL5/CCL3L1-CCR1) [14]. Moreover, Ryu et al. reported abnormal activity in the proliferation, antigen presentation, proteasome, and oxidative phosphorylation of extramedullary myeloma cells.

他们发现了新分子（PDIA6，LETM1），网络（UQCRB-PDIA6，STAT1-LETM1）和串扰对（CCL3/CCL5/CCL3L1-CCR1）[14]。此外，Ryu等人报道了髓外骨髓瘤细胞的增殖，抗原呈递，蛋白酶体和氧化磷酸化的异常活性。

Data availability

数据可用性

Data generated during this study have been deposited in the National Genomic Data Center [54] with the accession numbers HRA004197. All datasets that support the findings of the current study are available from the corresponding author upon reasonable request.

本研究期间产生的数据已保存在国家基因组数据中心（54），登录号为HRA004197。所有支持当前研究结果的数据集均可根据合理要求从通讯作者处获得。

Code availability

代码可用性

Codes could be accessed, along with the supporting data, upon reasonable request from Y.P.

根据Y.P.的合理要求，可以访问代码以及支持数据。

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Download referencesAcknowledgementsThis study was supported by grants from the National Natural Science Foundation of China (81920108004, 82270127, 82070175, 82370128 92253201, 32350026, and 22334005), the National Key Research and Development Program of China (2018YFA0107800, 2021YFA0909400), the Hunan Natural Science Foundation of China (2024JJ3037, 2022JJ30830, and 2022JJ30183), the Ambassador Program for Science and Technology Innovation in Hunan Province (2022RC3074), the Hunan Provincial Health Commission Research Program Project (20201179), the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (GZC20233178), the Fundamental Research Funds for Central Universities of the Central South University (No.

。

2023ZZTS0541), and Shenzhen Health Development Research and Data Management Center (0868-2344ZD1274F, sz20230199).Author informationAuthor notesThese authors contributed equally: Yanpeng Wang, Yuanliang Peng, Chaoying Yang.Authors and AffiliationsDepartment of Hematology, the Second Xiangya Hospital, School of Life Sciences, Central South University, Changsha, 410011, ChinaYanpeng Wang, Yuanliang Peng, Hongling Peng & Jing LiuHunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, 410011, ChinaYanpeng Wang, Yuanliang Peng, Chaoying Yang, Dehui Xiong, Zeyuan Wang, Xiaojuan Xiao & Jing LiuDepartment of Clinical Laboratory, the Affiliated Nanhua Hospital, University of South China, Hengyang, 421001, ChinaYanpeng WangShenzhen Health Development Research and Data Management Center, Shenzhen, 518028, ChinaXusheng WuAuthorsYanpeng WangView author publicationsYou can also search for this author in.

2023ZZTS0541）和深圳健康发展研究与数据管理中心（0868-2344ZD1274F，sz20230199）。。作者和附属机构中南大学生命科学学院湘雅第二医院血液科，长沙，410011，王艳鹏，彭元良，彭洪玲，刘靖湖南省中南大学基础与应用血液学重点实验室，长沙，410011，王艳鹏，彭元良，杨朝英，熊德辉，王泽元，肖娟，刘靖华南大学附属南华医院临床实验室，衡阳，421001，王艳鹏深圳健康发展研究与数据管理中心，深圳，518028，吴旭生作者王艳鹏观点作者出版物You也可以在中搜索此作者。

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PubMed Google ScholarContributionsJ.L., X.X., H.P. and X.W. designed experiments, analyzed the data, Y.W., Y.P., C.Y., D.X., and Z.W. performed research and acquired the data. J.L., X.X., Y.W. and Y.P. wrote the paper. J.L. revised the paper.Corresponding authorsCorrespondence to.

PubMed谷歌学术贡献。五十、 ，X.X.，H.P.和X.W.设计了实验，分析了数据，Y.W.，Y.P.，C.Y.，D.X。和Z.W.进行了研究并获得了数据。J、 L.，X.X.，Y.W.和Y.P.写了这篇论文。J、 L.修改了论文。通讯作者通讯。

Hongling Peng, Xusheng Wu, Xiaojuan Xiao or Jing Liu.Ethics declarations

彭洪玲、吴旭生、肖晓娟或刘静。道德宣言

Ethics approval

道德认可

All the samples of human MM patients used in the study were approved as per the ethical standards of the Ethics Committee of the School of Life Sciences of Central South University (approval No. 2019-1-11) and processed in accordance with the approved procedure of the committee. Animal protocols were reviewed and approved by the Department of Experimental Animal Science of Central South University (approval No.

本研究中使用的所有人类MM患者样本均按照中南大学生命科学学院伦理委员会的道德标准（批准号2019-1-11）进行了批准，并按照批准的程序进行了处理。委员会。中南大学实验动物科学系（批准号：。

CSU-2022-0001-0120) and all methods were performed in accordance with the relevant guidelines and regulations..

。。

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Reprints and permissionsAbout this articleCite this articleWang, Y., Peng, Y., Yang, C. et al. Single-cell sequencing analysis of multiple myeloma heterogeneity and identification of new theranostic targets.

转载和许可本文引用本文Wang，Y.，Peng，Y.，Yang，C。等人。多发性骨髓瘤异质性的单细胞测序分析和新的治疗诊断靶标的鉴定。

Cell Death Dis 15, 672 (2024). https://doi.org/10.1038/s41419-024-07027-4Download citationReceived: 15 April 2024Revised: 16 August 2024Accepted: 22 August 2024Published: 14 September 2024DOI: https://doi.org/10.1038/s41419-024-07027-4Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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