m1A regulator‑mediated methylation modifications and gene signatures and their prognostic value in multiple myeloma

Fu,Jiaqi; Han,Xingjun; Gao,Wei; Yu,Manya; Cui,Xing

doi:10.3892/etm.2024.12768

m1A regulator‑mediated methylation modifications and gene signatures and their prognostic value in multiple myeloma

Authors:
- Jiaqi Fu
- Xingjun Han
- Wei Gao
- Manya Yu
- Xing Cui
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Affiliations: Department of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China, Department of Preventive Treating Disease Center, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250001, P.R. China, Laboratory Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China, Department of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, P.R. China, Department of Oncology and Hematology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250001, P.R. China
Published online on: November 18, 2024 https://doi.org/10.3892/etm.2024.12768
Article Number: 18
Copyright: © Fu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

N¹‑methyladenosine (m1A), a methylation of RNA, is gaining attention for its role in diverse biological processes. However, the potential roles of m1A regulatory‑mediated methylation modifications in multiple myeloma (MM) remain unclear. The mRNA expression of m1A regulators in normal plasma (NP; n=9) and MM (n=174) bone marrow plasma cells was investigated and the m1A modification patterns of 559 MM samples based on the expression of 10 m1A‑related regulatory genes were comprehensively evaluated. Univariate Cox regression, Kaplan‑Meier survival curve, unsupervised clustering and gene enrichment analyses were used to explore the associations between m1A‑related regulatory genes and MM patient survival/prognosis. The m1A score model was subsequently constructed to quantify the m1A modification patterns of individual tumours, and its predictive performance was further assessed via receiver operating characteristic curves. Immunohistochemistry, Cell Counting Kit‑8, flow cytometry and m1A dot blot assays were performed to investigate the potential role of YTH domain‑containing family protein 2 (YTHDF2) in MM. Moreover, bioinformatics analysis was performed to predict the potential downstream regulatory mechanism of YTHDF2. In total, seven differentially expressed genes [tRNA methyltransferase 61A/B (TRMT61A/B), YTH N⁶‑methyladenosine RNA binding protein (YTHD)F1/F2/F3/C1 and Alkb homolog 1, histone H2A dioxygenase (ALKBH1)] were identified in MM samples compared with those in NP samples. The forest map and Kaplan‑Meier curve revealed that the expression of m1A‑related regulatory genes could be favourable prognostic factors for patients with MM. A total of three distinct m1A modification patterns were determined, and Cluster B exhibited the worst outcome, which was accompanied by increased expression of YTHDF2, tRNA methyltransferase 6 non‑catalytic subunit (TRMT6), tRNA methyltransferase 10 homolog C (TRMT10C) and TRMT61B. The m1Ascore model was subsequently constructed. A high m1A score was associated with clinical benefit and an improved treatment response. High expression of the reader protein YTHDF2 was associated with poor survival in patients with MM and was superior to other assessed proteins in terms of prognosis. Subsequent cell experiments demonstrated that YTHDF2 promoted the proliferation and inhibited the apoptosis of U266 cells. Notably, an evident increase in the m1A level was observed when YTHDF2 was overexpressed. A total of 150 genes related to YTHDF2 were identified, and these genes were enriched in the peroxisome proliferator‑activated receptor signalling pathway, protein export, positive regulation of protein targeting to the membrane, and gamma‑delta intraepithelial T‑cell differentiation. Serine and arginine rich splicing factor 10 (SRSF10) was subsequently selected because SRSF10 expression was significantly positively correlated with YTHDF2 expression and was also associated with poor prognosis in patients with MM. The present study revealed the modification patterns and high prognostic value of m1A regulators and demonstrated that the reader protein YTHDF2 is a potentially crucial target for MM.

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