m5C Regulator-mediated methylation modification clusters contribute to the immune microenvironment regulation of multiple myeloma

Hefei Ren; Chang Liu; Hongkun Wu; Zhenhua Wang; Sai Chen; Xiaomin Zhang; Jigang Ren; Huiying Qiu; Lin Zhou

doi:10.3389/fgene.2022.920164

m⁵C Regulator-mediated methylation modification clusters contribute to the immune microenvironment regulation of multiple myeloma

Front Genet. 2022 Aug 25:13:920164. doi: 10.3389/fgene.2022.920164. eCollection 2022.

Authors

Hefei Ren¹, Chang Liu¹, Hongkun Wu¹, Zhenhua Wang¹, Sai Chen¹, Xiaomin Zhang¹, Jigang Ren¹, Huiying Qiu², Lin Zhou¹

Affiliations

¹ Department of Laboratory Medicine, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, China.
² Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Background: Multiple myeloma (MM) is a hematological malignancy in which plasma cells proliferate abnormally. 5-methylcytosine (m⁵C) methylation modification is the primary epigenetic modification and is involved in regulating the occurrence, development, invasion, and metastasis of various tumors; however, its immunological functions have not been systematically described in MM. Thus, this study aimed to clarify the significance of m⁵C modifications and how the immune microenvironment is linked to m⁵C methylation in MM. Method: A total of 483 samples (60 healthy samples, 423 MM samples) from the Gene Expression Omnibus dataset were acquired to assess the expression of m⁵C regulators. A nomogram model was established to predict the occurrence of MM. We investigated the impact of m⁵C modification on immune microenvironment characteristics, such as the infiltration of immunocytes and immune response reactions. We then systematically evaluated three different m⁵C expression patterns to assess immune characteristics and metabolic functional pathways and established m⁵C-related differentially expressed genes (DEGs). In addition, biological process analysis was performed and an m⁵C score was constructed to identify potentially significant immunological functions in MM. Result: Differential expressions of m⁵C regulators were identified between healthy and MM samples. The nomogram revealed that m⁵C regulators could predict higher disease occurrence of MM. We identified three distinct m⁵C clusters with unique immunological and metabolic characteristics. Among the three different m⁵C clusters, cluster C had more immune characteristics and more metabolism-related pathways than clusters A and B. We analyzed 256 m⁵C-related DEGs and classified the samples into three different m⁵C gene clusters. Based on the m⁵C and m⁵C gene clusters, we calculated m⁵C scores and classified each patient into high- and low-m⁵C score groups. Conclusion: Our study demonstrated that m⁵C modification is involved in and contributes to the diversity and complexity of the immune microenvironment, which offers promise for the development of accurate therapeutic strategies.

Keywords: 5-methylcytosine; biological function; immune microenvironment; immune therapy; multiple myeloma.