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山东大学学报 (医学版) ›› 2021, Vol. 59 ›› Issue (10): 32-40.doi: 10.6040/j.issn.1671-7554.0.2021.0725

• 临床医学 • 上一篇    下一篇

基于单细胞测序分析急性髓系白血病患者骨髓免疫微环境的特点

王艳1,张宇卉1,胡耐博1,滕广帅1,周圆2,白洁1   

  1. 1. 天津医科大学第二医院血液科, 天津 300211;2.中国医学科学院血液病医院 中国医学科学院血液学研究所 实验血液学国家重点实验室, 天津 300020
  • 发布日期:2021-10-15
  • 通讯作者: 白洁. E-mail:janebai86@hotmail.com
  • 基金资助:
    国家自然科学基金(81770128,81970120)

Characteristics of bone marrow immune microenvironment in patients with acute myeloid leukemia based on single-cell RNA sequencing

WANG Yan1, ZHANG Yuhui1, HU Naibo1, TENG Guangshuai1, ZHOU Yuan2, BAI Jie1   

  1. 1. Department of Hematology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China;
    2. State Key Laboratory of Experimental Hematology, Institute of Hematology &
    Blood Diseases Hospital, National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences &
    Peking Union Medical College, Tianjin 300020, China
  • Published:2021-10-15

摘要: 目的 通过单细胞测序技术分析急性髓系白血病(AML)患者骨髓免疫微环境的组成情况,探讨不同类型免疫细胞的不同亚群在AML发生发展中的作用。 方法 检索基因表达数据库(GEO)中符合条件的scRNA-seq数据集(GSE116256),利用R语言的Seurat包对数据进行处理,利用SingleR包并参考既往研究对细胞亚群进行注释,计算不同类型免疫细胞的比例,寻找AML患者与正常对照组存在差异的细胞亚群并计算它们的差异基因(DEGs),对DEGs进行基因本体功能注释(GO)和京都基因与基因组百科全书富集分析(KEGG),明确存在差异的细胞亚群在AML疾病进程中的作用。 结果 与正常对照组相比, AML患者的造血祖细胞、单核细胞、NK/T细胞、树突状细胞和B细胞的亚群比例均发生不同程度改变。通过对差异基因进行功能富集发现,AML的单核细胞、树突状细胞、B细胞以及T细胞的增殖、分化、免疫调控及对肿瘤细胞的杀伤功能出现不同程度损伤。 结论 AML患者与健康人的免疫微环境存在较大差异,这些差异可能与AML的发生发展关系密切。

关键词: 急性髓系白血病, 单细胞测序, 骨髓微环境, 免疫细胞, 生物信息

Abstract: Objective To analyze the composition of bone marrow immune microenvironment in patients with acute myeloid leukemia(AML)by single cell sequencing technology, and to explore the role of different subsets of different types of immune cells in the occurrence and development of AML. Methods The scRNA-seq data(GSE116256)which met the requirements of this study were downloaded from GEO database and processed with the Seurat package of R language. The cell subsets were annotated by single R package and reference to previous studies, the proportion of different types of immune cells was calculated, and the differentially expressed genes(DEGs)of cell subsets between AML patients and normal controls were calculated. Gene ontology function annotation(GO)and Kyoto Encyclopedia of genes and genomes(KEGG)enrichment analysis on DEGs were performed to clarify the role of cell subsets in the progression of AML. Results Compared with the normal control group, AML patients had changed proportion of progenitor cells, monocytes, NK/T cells, dendritic cells and B cells. GO analysis indicated that the proliferation, differentiation, immune regulation and killing function of monocytes, dendritic cells, B cells and T cells were damaged. Conclusion There are big differences in the immune microenvironment between AML patients and healthy people, and these differences may be closely related to the occurrence and development of AML.

Key words: Acute myeloid leukemia, Single cell sequencing, Bone marrow microenvironment, Immune cells, Bioinformatics

中图分类号: 

  • R551.3
[1] Creutzig U, Kutny MA, Barr R, et al. Acute myelogenous leukemia in adolescents and young adults [J]. Pediatr Blood Cancer, 2018, 65(9): e27089.
[2] 张静, 何欢, 曾雪倩, 等. 急性髓系白血病耐药相关信号通路的研究进展[J]. 河北医学, 2021, 27(1): 167-170. ZHANG Jing, HE Huan, ZENG Xueqian, et al. Research progress on drug resistance related signaling pathways in acute myeloid leukemia [J]. Hebei Medicine, 2021, 27(1): 167-170.
[3] Cai SF, Levine RL. Genetic and epigenetic determinants of AML pathogenesis [J]. Semin Hematol, 2019, 56(2): 84-89.
[4] Nahas MR, Stroopinsky D, Rosenblatt J, et al. Hypomethylating agent alters the immune microenvironment in acute myeloid leukaemia(AML)and enhances the immunogenicity of a dendritic cell/AML vaccine [J]. Br J Haematol, 2019, 185(4): 679-690.
[5] Webster JA, Pratz KW. Acute myeloid leukemia in the elderly: therapeutic options and choice [J]. Leuk Lymphoma, 2018, 59(2): 274-287.
[6] Ma P, Xing M, Han L, et al. High PDL1 expression drives glycolysis via an Akt/mTOR/HIF1alpha axis in acute myeloid leukemia [J]. Oncol Rep, 2020, 43(3): 999-1009.
[7] Kamitani I, Saito T, Yokoyama H, et al. Successful bridge therapy of gilteritinib to cord blood transplantation in relapsed acute myeloid leukemia after bone marrow transplantation [J]. J Infect Chemother, 2021, 27(4): 639-641.
[8] Cheng Y, Wang X, Qi P, et al. Tumor microenvironmental competitive endogenous RNA network and immune cells act as robust prognostic predictor of acute myeloid leukemia [J]. Front Oncol, 2021, 11: 584884. doi: 10.3389/fonc.2021.584884.
[9] Chen HJ, Zhang S, Luo QD, et al. Research advance on the immune escape of acute myeloid leukemia—review [J]. J Exp Hematol, 2020, 28(4): 1429-1432.
[10] Leimkuhler NB, Schneider RK. Inflammatory bone marrow microenvironment [J]. Hematology Am Soc Hematol Educ Program, 2019, 2019(1): 294-302.
[11] Bruck O, Blom S, Dufva O, et al. Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML [J]. Leukemia, 2018, 32(7): 1643-1656.
[12] Guo R, Lu M, Cao F, et al. Single-cell map of diverse immune phenotypes in the acute myeloid leukemia microenvironment [J]. Biomark Res, 2021, 9(1): 15.
[13] Petti AA, Williams SR, Miller CA, et al. A general approach for detecting expressed mutations in AML cells using single cell RNA-sequencing [J]. Nat Commun, 2019, 10(1): 3660.
[14] Miles LA, Bowman RL, Merlinsky TR, et al. Single-cell mutation analysis of clonal evolution in myeloid malignancies [J]. Nature, 2020, 587(7834): 477-482.
[15] van Galen P, Hovestadt V, Wadsworth IM, et al. Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity[J]. Cell, 2019,176(6):1265-1281.
[16] Kantarjian HM, Kadia TM, DiNardo CD, et al. Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach [J]. Cancer, 2021, 127(8): 1186-1207.
[17] 刘姚姚, 杨福军, 刘超, 等. 骨髓微环境调控白血病干细胞的研究进展[J]. 现代肿瘤医学, 2018, 26(21): 3520-3523. LIU Yaoyao, YANG Fujun, LIU Chao, et al. Research progress of bone marrow microenvironment regulating leukemia stem cells [J]. Journal of Modern Oncology, 2018, 26(21): 3520-3523.
[18] Ugel S, Cane S, De Sanctis F, et al. Monocytes in the TUMOR Microenvironment [J]. Annu Rev Pathol, 2021, 16: 93-122. doi: 10.1146/annurev-pathmechdis-012418-013058.
[19] Shen CK, Huang BR, Yeh WL, et al. Regulatory effects of IL-1beta in the interaction of GBM and tumor-associated monocyte through VCAM-1 and ICAM-1 [J]. Eur J Pharmacol, 2021, 905: 174216. doi: 10.1016/j.ejphar.2021.174216.
[20] 江楚怡, 蔡晶, 王泽华, 等. 人类肿瘤中Tie2阳性单核巨噬细胞研究进展[J]. 肿瘤防治研究, 2021, 48(3): 314-318. JIANG Chuyi, CAI Jing, WANG Zehua, et al. Tie2 expressing monocytes/macrophages in human tumors [J]. Cancer Research on Prevention and Treatment, 2021, 48(3): 314-318.
[21] Anguille S, Van de Velde AL, Smits EL, et al. Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia [J]. Blood, 2017, 130(15): 1713-1721.
[22] 何易祥, 赵宇昊, 高昭, 等. B淋巴细胞及相关细胞因子在骨免疫系统中对破骨细胞分化的作用[J]. 中国组织工程研究, 2021, 25(29): 4709-4714. HE Yixiang, ZHAO Yuhao, GAO Zhao, et al. Effect of B lymphocytes and related cytokines on osteoclast differentiation in the osteoimmunology system [J]. Chinese Journal of Tissue Engineering Research. 2021, 25(29): 4709-4714.
[23] Oh DY, Kwek SS, Raju SS, et al. Intratumoral CD4+T cells mediate anti-tumor cytotoxicity in human bladder cancer [J]. Cell, 2020, 181(7): 1612-1625.
[24] Li H, van der Leun AM, Yofe I, et al. Dysfunctional CD8+T Cells form a proliferative, dynamically regulated compartment within human melanoma [J]. Cell, 2019, 176(4): 775-789.
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