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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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References

  1. Heuser M, Schlarmann C, Dobbernack V, Panagiota V, Wiehlmann L, Walter C, et al. Genetic characterization of acquired aplastic anemia by targeted sequencing. Haematologica. 2014;99(Sep):e165–167.

    Article  CAS  Google Scholar 

  2. Kulasekararaj AG, Jiang J, Smith AE, Mohamedali AM, Mian S, Gandhi S, et al. Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome. Blood. 2014;124(Oct):2698–704.

    Article  CAS  Google Scholar 

  3. Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, et al. Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. N. Engl J Med. 2015;373(Jul):35–47.

    Article  CAS  Google Scholar 

  4. Babushok DV, Perdigones N, Perin JC, Olson TS, Ye W, Roth JJ, et al. Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia. Cancer Genet. 2015;208(Apr):115–28.

    Article  CAS  Google Scholar 

  5. Hosokawa K, Mizumaki H, Elbadry MI, Saito C, Espinoza JL. Thi Thanh Dao A, et al. Clonal hematopoiesis by SLIT1-mutated hematopoietic stem cells due to a breakdown of the autocrine loop involving Slit1 in acquired aplastic anemia. Leukemia. 2019;33(Nov):2732–66.

    Article  Google Scholar 

  6. Tutelman PR, Aubert G, Milner RA, Dalal BI, Schultz KR, Deyell RJ. Paroxysmal nocturnal haemoglobinuria phenotype cells and leucocyte subset telomere length in childhood acquired aplastic anaemia. Br J Haematol. 2014;164(Mar):717–21.

    Article  CAS  Google Scholar 

  7. Kulagin A, Lisukov I, Ivanova M, Golubovskaya I, Kruchkova I, Bondarenko S, et al. Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two-centre prospective study. Br J Haematol. 2014;164(Feb):546–54.

    Article  CAS  Google Scholar 

  8. Maruyama H, Katagiri T, Kashiwase K, Shiina T, Sato-Otsubo A, Zaimoku Y, et al. Clinical significance and origin of leukocytes that lack HLA-A allele expression in patients with acquired aplastic anemia. Exp Hematol. 2016;44(Oct):931–9. e933

    Article  CAS  Google Scholar 

  9. Katagiri T, Sato-Otsubo A, Kashiwase K, Morishima S, Sato Y, Mori Y, et al. Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia. Blood. 2011;118(Dec):6601–9.

    Article  CAS  Google Scholar 

  10. Mizumaki H, Hosomichi K, Hosokawa K, Yoroidaka T, Imi T, Zaimoku Y, et al. A frequent nonsense mutation in exon 1 across certain HLA-A and -B alleles in leukocytes of patients with acquired aplastic anemia. Haematologica. 2021;106:1–9.

    Google Scholar 

  11. Elbadry MI, Mizumaki H, Hosokawa K, Espinoza JL, Nakagawa N, Chonabayashi K, et al. Escape hematopoiesis by HLA-B5401-lacking hematopoietic stem progenitor cells in men with acquired aplastic anemia. Haematologica. 2019;104(Oct):e447–e450.

    Article  CAS  Google Scholar 

  12. Zaimoku Y, Takamatsu H, Hosomichi K, Ozawa T, Nakagawa N, Imi T, et al. Identification of an HLA class I allele closely involved in the autoantigen presentation in acquired aplastic anemia. Blood. 2017;129(May):2908–16.

    Article  CAS  Google Scholar 

  13. Espinoza JL, Elbadry MI, Chonabayashi K, Yoshida Y, Katagiri T, Harada K, et al. Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack. Blood Adv. 2018;2(Feb):390–400.

    Article  CAS  Google Scholar 

  14. Young NS. Aplastic anemia. N. Engl J Med. 2018;379(Oct):1643–56.

    Article  CAS  Google Scholar 

  15. Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini MT, et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N. Engl J Med. 2009;361(Jul):478–88.

    Article  CAS  Google Scholar 

  16. Hosokawa K, Katagiri T, Sugimori N, Ishiyama K, Sasaki Y, Seiki Y, et al. Favorable outcome of patients who have 13q deletion: a suggestion for revision of the WHO ‘MDS-U’ designation. Haematologica. 2012;97(Dec):1845–9.

    Article  CAS  Google Scholar 

  17. Sugimori C, Chuhjo T, Feng X, Yamazaki H, Takami A, Teramura M, et al. Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood. 2006;107(Feb):1308–14.

    Article  CAS  Google Scholar 

  18. Gargiulo L, Papaioannou M, Sica M, Talini G, Chaidos A, Richichi B, et al. Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121(Apr):2753–61.

    Article  CAS  Google Scholar 

  19. Gargiulo L, Zaimoku Y, Scappini B, Maruyama H, Ohumi R, Luzzatto L, et al. Glycosylphosphatidylinositol-specific T cells, IFN-gamma-producing T cells, and pathogenesis of idiopathic aplastic anemia. Blood. 2017;129(Jan):388–92.

    Article  CAS  Google Scholar 

  20. Murakami Y, Kosaka H, Maeda Y, Nishimura J, Inoue N, Ohishi K, et al. Inefficient response of T lymphocytes to glycosylphosphatidylinositol anchor-negative cells: implications for paroxysmal nocturnal hemoglobinuria. Blood. 2002;100(Dec):4116–22.

    Article  CAS  Google Scholar 

  21. Parker CJ. The pathophysiology of paroxysmal nocturnal hemoglobinuria. Exp Hematol. 2007;35(Apr):523–33.

    Article  CAS  Google Scholar 

  22. Khurana S, Margamuljana L, Joseph C, Schouteden S, Buckley SM, Verfaillie CM. Glypican-3-mediated inhibition of CD26 by TFPI: a novel mechanism in hematopoietic stem cell homing and maintenance. Blood. 2013;121(Apr):2587–95.

    Article  CAS  Google Scholar 

  23. Hosokawa K, Sugimori C, Ishiyama K, Takamatsu H, Noji H, Shichishima T, et al. Establishment of a flow cytometry assay for detecting paroxysmal nocturnal hemoglobinuria-type cells specific to patients with bone marrow failure. Ann Hematol. 2018;97(Dec):2289–97.

    Article  CAS  Google Scholar 

  24. Katagiri T, Kawamoto H, Nakakuki T, Ishiyama K, Okada-Hatakeyama M, Ohtake S, et al. Individual hematopoietic stem cells in human bone marrow of patients with aplastic anemia or myelodysplastic syndrome stably give rise to limited cell lineages. Stem Cells. 2013;31(Mar):536–46.

    Article  CAS  Google Scholar 

  25. Notta F, Zandi S, Takayama N, Dobson S, Gan OI, Wilson G, et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science. 2016;351(Jan):aab2116.

    Article  Google Scholar 

  26. Yoroidaka T, Hosokawa K, Imi T, Katagiri T, Azuma F, Nakao S. Bystander Proliferation of Piga-Mutated Hematopoietic Progenitor Cells in Acquired Aplastic Anemia Patients Possessing HLA Class I Allele-Lacking Leukocytes. Blood. 2018;132(Suppl. 1):1308–1308.

    Article  Google Scholar 

  27. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48(Mar):452–8.

    Article  CAS  Google Scholar 

  28. Araten DJ, Boxer D, Zamechek L, Sherman E, Nardi M. Analysis of platelets by flow cytometry in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). Blood Cells Mol Dis. 2020;80(Feb):102372.

    Article  CAS  Google Scholar 

  29. Sanchez MJ, Muench MO, Roncarolo MG, Lanier LL, Phillips JH. Identification of a common T/natural killer cell progenitor in human fetal thymus. J Exp Med. 1994;180(Aug):569–76.

    Article  CAS  Google Scholar 

  30. El-Sherbiny YM, Kelly RJ, Hill A, Doody GM, Hillmen P, Cook GP. Altered natural killer cell subset homeostasis and defective chemotactic responses in paroxysmal nocturnal hemoglobinuria. Blood. 2013;122(Sep):1887–90.

    Article  CAS  Google Scholar 

  31. Imi T, Katagiri T, Hosomichi K, Zaimoku Y, Hoang Nguyen V, Nakagawa N, et al. Sustained clonal hematopoiesis by HLA-lacking hematopoietic stem cells without driver mutations in aplastic anemia. Blood Adv. 2018;2(May):1000–12.

    Article  CAS  Google Scholar 

  32. Sugimori C, Mochizuki K, Qi Z, Sugimori N, Ishiyama K, Kondo Y, et al. Origin and fate of blood cells deficient in glycosylphosphatidylinositol-anchored protein among patients with bone marrow failure. Br J Haematol. 2009;147(Oct):102–12.

    Article  CAS  Google Scholar 

  33. Tominaga R, Katagiri T, Kataoka K, Kataoka K, Wee RK, Maeda A, et al. Paroxysmal nocturnal hemoglobinuria induced by the occurrence of BCR-ABL in a PIGA mutant hematopoietic progenitor cell. Leukemia. 2016;30(May):1208–10.

    Article  CAS  Google Scholar 

  34. Takahashi N, Miura I, Saitoh K, Miura AB. Lineage involvement of stem cells bearing the philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence-activated cell sorting and fluorescence in situ hybridization. Blood. 1998;92(Dec):4758–63.

    Article  CAS  Google Scholar 

  35. Arends CM, Galan-Sousa J, Hoyer K, Chan W, Jager M, Yoshida K, et al. Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis. Leukemia. 2018;32(Sep):1908–19.

    Article  CAS  Google Scholar 

  36. Inoue N, Izui-Sarumaru T, Murakami Y, Endo Y, Nishimura J, Kurokawa K, et al. Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2006;108(Dec):4232–6.

    Article  CAS  Google Scholar 

  37. Shen W, Clemente MJ, Hosono N, Yoshida K, Przychodzen B, Yoshizato T, et al. Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. J Clin Invest. 2014;124(Oct):4529–38.

    Article  CAS  Google Scholar 

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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 35, 3257–3267 (2021). https://doi.org/10.1038/s41375-021-01202-8

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