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STEM CELL BIOLOGY

Hematopoietic stem progenitor cells lacking HLA differ from those lacking GPI-anchored proteins in the hierarchical stage and sensitivity to immune attack in patients with acquired aplastic anemia

Abstract

To characterize glycosylphosphatidylinositol-anchored protein-deficient (GPI[−]) and HLA-class I allele-lacking (HLA[−]) hematopoietic stem progenitor cells (HSPCs) in acquired aplastic anemia (AA), we studied the peripheral blood (PB) of 56 AA patients in remission who possessed both (n = 13, Group A) or either GPI(−) (n = 34, Group B) and HLA(−) (n = 9, Group C) cell populations. Seventy-seven percent (10/13) of Group A had HLA(−) cells in all lineages of PB cells, including platelets, while only 23% (3/13) had GPI(−) cells in all lineages, and the median percentage of HLA(−) granulocytes in the total granulocytes (21.2%) was significantly higher than that of GPI(−) granulocytes (0.28%, P < 0.05). The greater lineage diversity in HLA(−) cells than in GPI(−) cells was also seen when Group B and Group C were compared. Longitudinal studies of seven patients in Group A showed a gradual decrease in the percentage of HLA(−) granulocytes, with a reciprocal increase in the GPI(−) granulocytes in four patients responding to cyclosporine (CsA) and an increase in the HLA(−) granulocytes with a stable or declining GPI(−) granulocytes in three patients in sustained remission off CsA therapy. These findings suggest that HLA(−) HSPCs differ from GPI(−) HSPCs in the hierarchical stage and sensitivity to immune attack in AA.

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Fig. 1: Lineage diversity in aplastic anemia patients who possessed both HLA(−) and GPI(−) cells.
Fig. 2: Lineage diversity and clone sizes in aplastic anemia patients with HLA(−) and GPI(−) cells.
Fig. 3: Lineage correlation with granulocytes in GPI(−) and HLA(−) cells.
Fig. 4: Chronological changes in HLA(−) granulocytes and GPI(−) granulocytes associated with IST.

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Acknowledgements

This work was supported by MEXT KAKENHI (Grant-in-Aid for Scientific Research (B), Grant Number: 24390243) to S.N., MEXT KAKENHI (Grant-in-Aid for Young Scientists (B), Grant Number: 26860363) to T.K., MEXT KAKENHI (Grant-in-Aid for Young Scientists, Grant Number: 17K16184 and 19K17823) to K.H., MEXT KAKENHI (Grant-in-Aid for Scientific Research (C), Grant Number: 18K08318) to H.Y., Hokkoku Foundation for Cancer Research to T.K and K.H. The authors thank the patients and donors and their physicians for contributing to this study and the Advanced Preventive Medical Sciences Research Center, Kanazawa University for the use of facilities. We thank Prof. Hiroshi Kawamoto for careful reading of the manuscript. T.Y. is a PhD candidate at Kanazawa University and this work is submitted in partial fulfillment of the requirements for the PhD.

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T.Y., K.H., T.I., H.M., T.K., K.I., H.Y., and S.N. collected clinical data and blood samples. T.Y. performed flow cytometry. F.A. performed HLA genotyping. T.Y. performed cell sorting. Y.N., S.O. performed deep sequencing. T.Y., K.H., and S.N. designed the research and wrote the manuscript. All authors critically reviewed the manuscript and checked the final version. T.Y. and K.H. contributed equally to this work.

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Correspondence to Shinji Nakao.

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Yoroidaka, T., Hosokawa, K., Imi, T. et al. Hematopoietic stem progenitor cells lacking HLA differ from those lacking GPI-anchored proteins in the hierarchical stage and sensitivity to immune attack in patients with acquired aplastic anemia. Leukemia (2021). https://doi.org/10.1038/s41375-021-01202-8

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