三维基因组学技术在多发性骨髓瘤的应用研究
Research on the Application of 3D Genomics Technology in Multiple Myeloma
DOI: 10.12677/acm.2025.15113130, PDF,    科研立项经费支持
作者: 陈 明, 陈孟斯, 王 悦, 刘海波：成都中医药大学临床医学院，四川 成都；张开基：成都市第一人民医院风湿血液科，四川 成都
关键词: 三维基因组学技术；层级结构；多发性骨髓瘤；异质性；3D Genomic Technologies； Hierarchical Structure； Multiple Myeloma； Heterogeneity
摘要: 三维基因组学技术能够特异性展示基因远程调控元件的空间互作关系，揭示线性基因组无法解释的基因调控关系，有利于解析基因空间构象变化、发现新的基因靶点和指导新药研发。多发性骨髓瘤(Multiple Myeloma, MM)是浆细胞恶性克隆的增殖性疾病，肿瘤细胞具有高度异质性，且在MM初诊、治疗和复发过程中不断发生克隆演变，因此掌握基因空间构象改变与基因调控变化的关系至关重要。本文结合三维基因组学技术理论基础、多发性骨髓瘤的基因异质性特点与三维基因组学技术在多发性骨髓瘤的应用，进一步探讨三维基因组学技术应用于多发性骨髓瘤的未来发展方向。
Abstract: Three-dimensional genomics technology can specifically display the spatial interaction relationship of remote regulatory elements of genes, reveal the gene regulatory relationships that cannot be explained by linear genomes, and is conducive to the analysis of gene spatial conformation changes, the discovery of new gene targets, and the guidance of new drug development. Multiple myeloma (MM) is a proliferative disease of malignant plasma cell clones. Tumor cells have high heterogeneity and continuously undergo clonal evolution during the initial diagnosis, treatment, and recurrence of MM. Therefore, it is crucial to understand the relationship between gene spatial conformation changes and gene regulatory changes. This article combines the theoretical basis of three-dimensional genomics technology, the gene heterogeneity characteristics of multiple myeloma, and the application of three-dimensional genomics technology in multiple myeloma to further explore the future development direction of three-dimensional genomics technology in multiple myeloma.
文章引用：陈明, 陈孟斯, 王悦, 刘海波, 张开基. 三维基因组学技术在多发性骨髓瘤的应用研究[J]. 临床医学进展, 2025, 15(11): 553-563. https://doi.org/10.12677/acm.2025.15113130

参考文献

[1] Mirny, L. and Dekker, J. (2022) Mechanisms of Chromosome Folding and Nuclear Organization: Their Interplay and Open Questions. Cold Spring Harbor Perspectives in Biology, 14, a040147. [Google Scholar] [CrossRef] [PubMed]
[2] Zhou, Q., Cheng, S., Zheng, S., Wang, Z., Guan, P., Zhu, Z., et al. (2023) Chromloops: A Comprehensive Database for Specific Protein-Mediated Chromatin Loops in Diverse Organisms. Nucleic Acids Research, 51, D57-D69. [Google Scholar] [CrossRef] [PubMed]
[3] Ahn, J.H., Davis, E.S., Daugird, T.A., Zhao, S., Quiroga, I.Y., Uryu, H., et al. (2021) Phase Separation Drives Aberrant Chromatin Looping and Cancer Development. Nature, 595, 591-595. [Google Scholar] [CrossRef] [PubMed]
[4] Misteli, T. (2020) The Self-Organizing Genome: Principles of Genome Architecture and Function. Cell, 183, 28-45. [Google Scholar] [CrossRef] [PubMed]
[5] Guo, Y., Xu, Q., Canzio, D., Shou, J., Li, J., Gorkin, D.U., et al. (2015) CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/promoter Function. Cell, 162, 900-910. [Google Scholar] [CrossRef] [PubMed]
[6] Dixon, J.R., Selvaraj, S., Yue, F., Kim, A., Li, Y., Shen, Y., et al. (2012) Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions. Nature, 485, 376-380. [Google Scholar] [CrossRef] [PubMed]
[7] Hildebrand, E.M. and Dekker, J. (2020) Mechanisms and Functions of Chromosome Compartmentalization. Trends in Biochemical Sciences, 45, 385-396. [Google Scholar] [CrossRef] [PubMed]
[8] Sehgal, N., Fritz, A.J., Morris, K., Torres, I., Chen, Z., Xu, J., et al. (2014) Gene Density and Chromosome Territory Shape. Chromosoma, 123, 499-513. [Google Scholar] [CrossRef] [PubMed]
[9] Rosin, L.F., Crocker, O., Isenhart, R.L., Nguyen, S.C., Xu, Z. and Joyce, E.F. (2019) Chromosome Territory Formation Attenuates the Translocation Potential of Cells. eLife, 8, e49553 [Google Scholar] [CrossRef] [PubMed]
[10] Hosea, R., Hillary, S., Naqvi, S., Wu, S. and Kasim, V. (2024) The Two Sides of Chromosomal Instability: Drivers and Brakes in Cancer. Signal Transduction and Targeted Therapy, 9, Article No. 75. [Google Scholar] [CrossRef] [PubMed]
[11] Gridina, M. and Fishman, V. (2022) Multilevel View on Chromatin Architecture Alterations in Cancer. Frontiers in Genetics, 13, Article 1059617. [Google Scholar] [CrossRef] [PubMed]
[12] 肖亦舒, 杜乐, 任立成. 染色体构象捕获技术及其衍生高通量技术发展与展望[J]. 基因组学与应用生物学, 2022, 41(Z2): 2271-2281.
[13] 杨琬婷, 杨磊, 王世强. 三维基因组测序技术发展[J]. 生命科学, 2019, 31(1): 1-8.
[14] 王舜泽, 江丰, 朱东丽, 等. Hi-C技术在三维基因组学和疾病致病机理研究中的应用[J]. 遗传, 2023, 45(4): 279-294.
[15] Nagano, T., Lubling, Y., Stevens, T.J., Schoenfelder, S., Yaffe, E., Dean, W., et al. (2013) Single-Cell Hi-C Reveals Cell-to-Cell Variability in Chromosome Structure. Nature, 502, 59-64. [Google Scholar] [CrossRef] [PubMed]
[16] Mifsud, B., Tavares-Cadete, F., Young, A.N., Sugar, R., Schoenfelder, S., Ferreira, L., et al. (2015) Mapping Long-Range Promoter Contacts in Human Cells with High-Resolution Capture Hi-C. Nature Genetics, 47, 598-606. [Google Scholar] [CrossRef] [PubMed]
[17] Hsieh, T.S., Fudenberg, G., Goloborodko, A. and Rando, O.J. (2016) Micro-C XL: Assaying Chromosome Conformation from the Nucleosome to the Entire Genome. Nature Methods, 13, 1009-1011. [Google Scholar] [CrossRef] [PubMed]
[18] Hong, P., Jiang, H., Xu, W., Lin, D., Xu, Q., Cao, G., et al. (2020) The DLO Hi-C Tool for Digestion-Ligation-Only Hi-C Chromosome Conformation Capture Data Analysis. Genes, 11, Article 289. [Google Scholar] [CrossRef] [PubMed]
[19] Fullwood, M.J., Liu, M.H., Pan, Y.F., Liu, J., Xu, H., Mohamed, Y.B., et al. (2009) An Oestrogen-Receptor-α-Bound Human Chromatin Interactome. Nature, 462, 58-64. [Google Scholar] [CrossRef] [PubMed]
[20] Mumbach, M.R., Rubin, A.J., Flynn, R.A., Dai, C., Khavari, P.A., Greenleaf, W.J., et al. (2016) HiChIP: Efficient and Sensitive Analysis of Protein-Directed Genome Architecture. Nature Methods, 13, 919-922. [Google Scholar] [CrossRef] [PubMed]
[21] Liang, D., Li, X., Bai, S., et al. (2024) Clinical Outcome of Induction Treatment in the Era of Novel Agents and the Impact of the Number of High-Risk Cytogenetic Abnormalities (HRA) on Prognosis of Patients with Newly Diagnosed Multiple Myeloma (NDMM): Insights from a Multicenter Study. Cancer Medicine, 13, e70270.
[22] Swan, D., Madduri, D. and Hocking, J. (2024) CAR-T Cell Therapy in Multiple Myeloma: Current Status and Future Challenges. Blood Cancer Journal, 14, Article No. 206. [Google Scholar] [CrossRef] [PubMed]
[23] 郝牧, 邱录贵. 多发性骨髓瘤肿瘤生物学研究进展[J]. 中国细胞生物学学报, 2022, 44(1): 111-119.
[24] 吴春晓, 曾招, 王琴荣, 等. 伴有染色体碎裂化异常的多发性骨髓瘤3例[J]. 中华血液学杂志, 2022, 43(12): 1034-1038
[25] 中国抗癌协会血液肿瘤专业委员会骨髓瘤与浆细胞疾病学组, 中国临床肿瘤学会多发性骨髓瘤专家委员会, 邱录贵, 等. 高危多发性骨髓瘤诊断与治疗中国专家共识(2024年版) [J]. 中华血液学杂志, 2024, 45(5): 430-435
[26] Liu, X., Jia, S., Chu, Y., Tian, B., Gao, Y., Zhang, C., et al. (2022) Chromosome 1q21 Gain Is an Adverse Prognostic Factor for Newly Diagnosed Multiple Myeloma Patients Treated with Bortezomib-Based Regimens. Frontiers in Oncology, 12, Article 938550. [Google Scholar] [CrossRef] [PubMed]
[27] Schavgoulidze, A., Talbot, A., Perrot, A., Cazaubiel, T., Leleu, X., Manier, S., et al. (2023) Biallelic Deletion of 1p32 Defines Ultra-High-Risk Myeloma, but Monoallelic Del(1p32) Remains a Strong Prognostic Factor. Blood, 141, 1308-1315. [Google Scholar] [CrossRef] [PubMed]
[28] Avet-Loiseau, H., Davies, F.E., Samur, M.K., et al. (2025) International Myeloma Society/International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma. Journal of Clinical Oncology, 2025, JCO2401893.
[29] Kim, S.J., Shin, H., Lee, H., Kim, N.K.D., Yun, J.W., Hwang, J.H., et al. (2016) Recurrent Mutations of MAPK Pathway Genes in Multiple Myeloma but Not in Amyloid Light-Chain Amyloidosis. Oncotarget, 7, 68350-68359. [Google Scholar] [CrossRef] [PubMed]
[30] Li, N., Lin, P., Zuo, Z., You, M.J., Shuai, W., Orlowski, R., et al. (2023) Plasma Cell Myeloma with RAS/BRAF Mutations Is Frequently Associated with a Complex Karyotype, Advanced Stage Disease, and Poorer Prognosis. Cancer Medicine, 12, 14293-14304. [Google Scholar] [CrossRef] [PubMed]
[31] Rustad, E.H., Yellapantula, V., Leongamornlert, D., Bolli, N., Ledergor, G., Nadeu, F., et al. (2020) Timing the Initiation of Multiple Myeloma. Nature Communications, 11, Article No. 1917. [Google Scholar] [CrossRef] [PubMed]
[32] Maura, F., Rajanna, A.R., Ziccheddu, B., Poos, A.M., Derkach, A., Maclachlan, K., et al. (2024) Genomic Classification and Individualized Prognosis in Multiple Myeloma. Journal of Clinical Oncology, 42, 1229-1240. [Google Scholar] [CrossRef] [PubMed]
[33] Alberge, J., Dutta, A.K., Poletti, A., Coorens, T.H.H., Lightbody, E.D., Toenges, R., et al. (2025) Genomic Landscape of Multiple Myeloma and Its Precursor Conditions. Nature Genetics, 57, 1493-1503. [Google Scholar] [CrossRef] [PubMed]
[34] 邵青, 付蓉. 长链非编码RNA在多发性骨髓瘤中的作用研究进展[J]. 中华血液学杂志, 2018, 39(7): 609-611.
[35] Statello, L., Guo, C., Chen, L. and Huarte, M. (2020) Gene Regulation by Long Non-Coding RNAs and Its Biological Functions. Nature Reviews Molecular Cell Biology, 22, 96-118. [Google Scholar] [CrossRef] [PubMed]
[36] 贺玉钦, 高文, 陈文明. 长链非编码RNA在多发性骨髓瘤发生发展中的作用[J]. 中国肿瘤临床, 2019, 46(12): 640-644.
[37] Corre, J., Munshi, N. and Avet-Loiseau, H. (2015) Genetics of Multiple Myeloma: Another Heterogeneity Level? Blood, 125, 1870-1876. [Google Scholar] [CrossRef] [PubMed]
[38] 王轶, 安刚, 邱录贵. 多发性骨髓瘤克隆演变研究进展[J]. 中华血液学杂志, 2021, 42(7): 611-615.
[39] Yan, Y., Qin, X., Liu, J., Fan, H., Yan, W., Liu, L., et al. (2022) Clonal Phylogeny and Evolution of Critical Cytogenetic Aberrations in Multiple Myeloma at Single-Cell Level by QM-FISH. Blood Advances, 6, 441-451. [Google Scholar] [CrossRef] [PubMed]
[40] 许婧钰, 王轶, 邱录贵, 等. 多发性骨髓瘤遗传学异常和克隆演变[J]. 中国细胞生物学学报, 2022, 44(1): 145-152.
[41] Salomon-Perzyński, A., Jamroziak, K. and Głodkowska-Mrówka, E. (2021) Clonal Evolution of Multiple Myeloma—Clinical and Diagnostic Implications. Diagnostics, 11, Article 1534. [Google Scholar] [CrossRef] [PubMed]
[42] 何旎涵, 周文. 多发性骨髓瘤细胞与骨髓微环境互作机制研究进展[J]. 四川大学学报(医学版), 2023, 54(3): 475-481.
[43] Boulogeorgou, K., Papaioannou, M., Chatzileontiadou, S., Georgiou, E., Fola, A., Tzorakoleftheraki, S., et al. (2025) Unveiling Extramedullary Myeloma Immune Microenvironment: A Systematic Review. Cancers, 17, Article 1081. [Google Scholar] [CrossRef] [PubMed]
[44] Sonugür, F.G. and Akbulut, H. (2019) The Role of Tumor Microenvironment in Genomic Instability of Malignant Tumors. Frontiers in Genetics, 10, Article 1063. [Google Scholar] [CrossRef] [PubMed]
[45] Mo, C.K., Liu, J., Chen, S., Storrs, E., Targino da Costa, A.L.N., Houston, A., et al. (2024) Tumour Evolution and Microenvironment Interactions in 2D and 3D Space. Nature, 634, 1178-1186. [Google Scholar] [CrossRef] [PubMed]
[46] Binder, M., Szalat, R.E., Talluri, S., Fulciniti, M., Avet-Loiseau, H., Parmigiani, G., et al. (2024) Bone Marrow Stromal Cells Induce Chromatin Remodeling in Multiple Myeloma Cells Leading to Transcriptional Changes. Nature Communications, 15, Article No. 4139. [Google Scholar] [CrossRef] [PubMed]
[47] Wu, P., Li, T., Li, R., Jia, L., Zhu, P., Liu, Y., et al. (2017) 3D Genome of Multiple Myeloma Reveals Spatial Genome Disorganization Associated with Copy Number Variations. Nature Communications, 8, Article No. 1937. [Google Scholar] [CrossRef] [PubMed]
[48] Zhang, K., Chen, M., Chen, M., Wang, Y., Liu, H., Li, Y., et al. (2025) The 3D Genome of Plasma Cells in Multiple Myeloma. Scientific Reports, 15, Article No. 19331. [Google Scholar] [CrossRef] [PubMed]
[49] 王悦, 陈孟斯, 陈明, 等. 两例不同核型多发性骨髓瘤标本的三维基因组特征分析[J]. 中国输血杂志, 2024, 37(11): 1247-1255+1263.
[50] Xiong, S., Zhou, J., Tan, T.K., Chung, T., Tan, T.Z., Toh, S.H., et al. (2024) Super Enhancer Acquisition Drives Expression of Oncogenic PPP1R15B That Regulates Protein Homeostasis in Multiple Myeloma. Nature Communications, 15, Article No. 6810. [Google Scholar] [CrossRef] [PubMed]
[51] Wall, B.P.G., Nguyen, M., Harrell, J.C. and Dozmorov, M.G. (2025) Machine and Deep Learning Methods for Predicting 3D Genome Organization. In: Methods in Molecular Biology, Springer, 357-400. [Google Scholar] [CrossRef] [PubMed]

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