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Transcriptional heterogeneity of clonal plasma cells and immune evasion in immunoglobulin light chain amyloidosis

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Abstract

Immunoglobulin light chain amyloidosis (AL amyloidosis) is characterized by the presence of B cells producing amyloidogenic immunoglobulin light chains (LCs). The low frequency of aberrant B cells in AL is often masked by a polyclonal B cell background, making it difficult for treatment. We analyzed the single-cell RNA sequencing data from GEO database to compare the plasma cell (PCs) in four individuals with AL amyloidosis, one AL subject after treatment, and six healthy controls. High interindividual variability in AL-derived PCs in their expression pattern of known overexpressed genes in multiple myeloma and their usage of V regions in LCs was demonstrated. We also found overexpression of MHC class I molecules as one of the common features of clonal PCs in individuals with AL amyloidosis. Significantly reduced frequencies of circulating natural killer (NK) cells were also observed in a small cohort of AL patients when compared to healthy controls. These data demonstrate that aberrant PCs in AL has a highly diverse transcriptome, an upregulation of MHC, and a dampened capability of immunosurveillance by reduction of circulating NK frequencies. The analysis of clonal PCs at single cell level may provide a better approach for precise molecular profiling and diagnosis of AL amyloidosis.

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Abbreviations

AL:

Immunoglobulin light chain

BM:

Bone marrow

DEG:

Differentially expressed gene

ER:

Endoplasmic reticulum

LC:

Light chain

MGUS:

Monoclonal gammopathy of undetermined significance

MM:

Multiple myeloma

NK:

Natural killer

PC:

Plasma cell

scRNA-seq:

Single-cell RNA sequencing

UMAP:

Uniform manifold approximation and projection

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Acknowledgements

This work was supported by grants from the National Key Research and Development Program of China (2017YFA0104500), the National Natural Science Foundation of China (91853202, J.L.; 32070897, 31671244, 31872734, Q.G.), the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81621001), Beijing Natural Science Foundation (7202079), the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences, 2018PT31039.

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Author notes

  1. Yujia Wang and Lushuang Xu have contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China

    Yujia Wang, Lushuang Xu, Yuzhe Hu, Lixue Jin, Lijun Yang, Pingzhang Wang & Qing Ge

  2. Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital and Institute of Hematology, Beijing, 100044, China

    Yang Liu, Xiaojun Huang & Jin Lu

  3. School of Life Sciences, Center for Bioinformatics, Peking University, Beijing, 100871, China

    Qiang Shi

  4. Translational Stem Cell Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China

    Kunshan Zhang

  5. Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, 100191, China

    Qing Ge

  6. Collaborative Innovation Center of Haematology, Soochow University, Suzhou, Jiangsu, China

    Jin Lu

  7. Peking University Health Sciences Center, 38 Xue Yuan Road, Beijing, 100191, China

    Qing Ge

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  1. Yujia Wang
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Contributions

Y.W. and L.X. did all the experiments. Y.W. prepared Figs. 1, 2, 3, 4, L.X. prepared Fig. 5, Y.L., Y.H., Q.S., L.J., L.Y. provided essential help for all the data analysis, sample preparation, and detection. P.W., K.Z., X.H. provided critical opinion on data analysis and manuscript preparation. Q.G. and J.L. wrote the manuscript.

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Correspondence to Qing Ge or Jin Lu.

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Wang, Y., Xu, L., Liu, Y. et al. Transcriptional heterogeneity of clonal plasma cells and immune evasion in immunoglobulin light chain amyloidosis. Int J Hematol 113, 231–242 (2021). https://doi.org/10.1007/s12185-020-03016-3

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