Revised International Staging System (R-ISS) stage-dependent analysis uncovers oncogenes and potential immunotherapeutic targets in multiple myeloma

Abstract
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Abstract

Multiple myeloma (MM) accounts for ~10% of all haematologic malignancies. Little is known about high intratumour heterogeneities in patients stratified by the Revised International Staging System (R-ISS). Herein, we constructed a single-cell transcriptome atlas to compare differential expression patterns among stages. We found that a novel cytotoxic plasma cell (PC) population exhibited with NKG7 positive was obviously enriched in stage II patients. Additionally, a malignant plasma cell population with significantly elevated expression of MKI67 and PCNA was associated with unfavourable prognosis and Epstein-Barr virus (EBV) infection in our collected samples. Moreover, Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) was found and verified to promote proliferation of MM cell lines, suggesting RRM2 may serve as a detrimental marker in MM. The percentages of CD8⁺ T cells and NKT cells decreased along with R-ISS stages, reflecting the plasticity of the tumour immune microenvironment. Importantly, their crosstalks with myeloid cells and PC identified several potential immunotargets such as SIRPA-CD47, and CD74-MIF, respectively. Collectively, this study provided an R-ISS-related single-cell MM atlas and revealed the clinical significance of novel PC clusters, as well as potential immunotargets in MM progression.

Data availability

Sequencing data have been deposited in GEO under accession code GSE176131.

The following data sets were generated

1. Zhong L
2. et al
(2022) Identification of heterogeneous networks and plasma-monocytes crosstalks in multiple myeloma stratified by R-ISS system through single-cell sequencing
NCBI Gene Expression Omnibus, GSE176131.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE176131

The following previously published data sets were used

1. Chng WJ
2. Huang GF
3. Chung TH
4. Ng SB et al
(2011) Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma
NCBI Gene Expression Omnibus, GSE6477.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc= GSE6477
(2018) Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma.
NCBI Gene Expression Omnibus, GSE117156.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE117156

Article and author information

Author details

Bo Gong

Department of Health Management, University of Electronic Science and Technology of China, ChengDu, China

For correspondence
gongbo2007@hotmail.com

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2763-6829
Ling Zhong

Department of Health Management, University of Electronic Science and Technology of China, ChengDu, China

Competing interests
The authors declare that no competing interests exist.
Peng Hao

Department of Orthopaedics, University of Electronic Science and Technology of China, ChengDu, China

Competing interests
The authors declare that no competing interests exist.
Qian Zhang

Department of Health Management, University of Electronic Science and Technology of China, ChengDu, China

Competing interests
The authors declare that no competing interests exist.
Tao Jiang

Department of Hematology, University of Electronic Science and Technology of China, ChengDu, China

Competing interests
The authors declare that no competing interests exist.
Huan Li

Department of Health Management, University of Electronic Science and Technology of China, ChengDu, China

Competing interests
The authors declare that no competing interests exist.
Jialing Xiao

Department of Health Management, University of Electronic Science and Technology of China, ChengDu, China

Competing interests
The authors declare that no competing interests exist.
Chenglong Li

Department of Hematology, University of Electronic Science and Technology of China, ChengDu, China

Competing interests
The authors declare that no competing interests exist.
Lan Luo

Chengdu University of Traditional Chinese Medicine, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Ping Shuai

Department of Health Management, University of Electronic Science and Technology of China, ChengDu, China

Competing interests
The authors declare that no competing interests exist.
Liang Wang

Department of Health Management, University of Electronic Science and Technology of China, ChengDu, China

Competing interests
The authors declare that no competing interests exist.
Yuping Liu

Department of Health Management, University of Electronic Science and Technology of China, ChengDu, China

Competing interests
The authors declare that no competing interests exist.
Yi Shi

Department of Health Management, University of Electronic Science and Technology of China, ChengDu, China

Competing interests
The authors declare that no competing interests exist.
Wei Zhang

Department of Orthopaedics, University of Electronic Science and Technology of China, ChengDu, China

For correspondence
zhangwspine@163.com

Competing interests
The authors declare that no competing interests exist.

Funding

National Natural Science Foundation of China (Youth Funds,82002212)

Ling Zhong

Science & Technology Department of Sichuan Province (Applied Basic Research,2022YFS0100)

Peng Hao

Chengdu Science and Technology Bureau (Applied Basic Research,2019-YF05-00572-SN)

Ling Zhong

China Postdoctoral Science Foundation (general program，2019M663567)

Ling Zhong

UESTC (Basic scientific research,ZYGX2020J024)

Ling Zhong

UESTC (Medicine-engineering interdisciplinary,ZYGX2021YGLH006)

Ling Zhong

Science &Technology Department of Sichuan Province (Outstanding Youth Fund，2022JDTD0024)

Bo Gong

Chengdu Science and Technology Bureau (Applied Basic Research,2022-YF05-01625-SN)

Bo Gong

Sichuan cadre health care project (Sichuan cadre health care project,2022-216)

Wei Zhang

UESTC (Medicine-engineering interdisciplinary,ZYGX2021YGLH204)

Wei Zhang

The roles of the funders were to do single cell sequence, analysis data, and verify the conclusions.

Ethics

Human subjects: Written informed consents were obtained from all subjects. All experimental procedures were approved by the Medical ethics committee of Sichuan Provincial People's Hospital and carried out in accordance with the principles of the Declaration of Helsinki. ALL of the patients signed the informed consent containing contact Information, the purpose of the study, risks and benefits from this study, consent to publish the manuscript. The protocol numbers was 2020-240.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.