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

Elife. 2022 Oct 31:11:e75340. doi: 10.7554/eLife.75340.


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 PC 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.

Keywords: EBV infection; NKG7; R-ISS; RRM2; Revised International Staging System; cancer biology; human; multiple myeloma.

Plain language summary

Multiple myeloma is a type of bone cancer. It affects the immune cells that make antibodies, known as plasma cells. These immune cells live in the bone marrow. As with many types of cancer, the chance of survival is highest when multiple myeloma is diagnosed early. It has three stages, labelled I, II, and III. People with stage I or II disease have better outcomes than those with stage III, but the exact reasons are unclear. Bone marrow contains lots of different types of cells, which can affect the growth of a tumour. These include cancer-targeting cells, called killer T-cells, and cancer-supporting cells called myeloid cells. Understanding these cells and how they interact could shed light on the different stages of multiple myeloma. One way to do this is to use single cell sequencing, which looks at the genes in use inside each cell at any one time. Zhong, Hao, Zhang, Jiang et al. examined the bone marrow of two healthy donors and nine people with different stages of multiple myeloma. This revealed two new groups of plasma cells. One group, highest in stage II patients, was protective, with the potential to kill cancer cells. The other, highest in people with more aggressive disease, was harmful, with the potential to divide rapidly. The sequencing also identified molecules that might be useful drug targets for the future. These included a gene that drove growth in the dangerous plasma cells, and several that might help tumours escape from the immune system. It is becoming increasingly clear that the environment around a tumour has a huge role to play in its progression. Understanding how this environment changes over time could aid in the development of more targeted treatments. The next step is to find out more about the molecules identified here.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes
  • Epstein-Barr Virus Infections*
  • Herpesvirus 4, Human
  • Humans
  • Immunotherapy
  • Multiple Myeloma* / genetics
  • Multiple Myeloma* / therapy
  • Neoplasm Staging
  • Oncogenes
  • Tumor Microenvironment

Associated data

  • GEO/GSE176131
  • GEO/GSE6477
  • GEO/GSE117156

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.