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<p>Acquired aplastic anemia (AA) is an immune-mediated bone marrow failure caused by autoreactive cytotoxic T lymphocytes targeting hematopoietic stem progenitor cells (HSPCs). Approximately 30% of AA patients exhibit leukocytes lacking HLA class I alleles (HLA[-]). In addition to this direct immune assault, the pathogenesis of AA is thought to involve indirect suppression mediated by the proinflammatory cytokine interferon-gamma (IFN-γ). Using HSPCs derived from induced pluripotent stem cells (iPSCs) with different HLA genotypes, HLA(-) HSPCs were found to be resistant to the suppressive effects of IFN-γ, whereas IFN-γ effectively suppressed the growth and development of HSPCs expressing HLA class I molecules. Further analysis showed that, in contrast to HLA(-) HSPCs, WT HSPCs showed enhanced CD119 expression in response to IFN-γ, activating downstream signaling pathways that promote apoptosis, suggesting that transcription factors involved in the apoptotic pathway following IFN-γ stimulation are differentially expressed between WT and HLA(-) HSPCs. Notably, IFN-γ stimulation reduced the expression of pSTAT3, a key regulator of apoptosis, in WT HSPCs, whereas its expression was elevated in HLA(-) HSPCs. In conclusion, this study showed that the selective hematopoietic inhibition of HSPCs by IFN-γ likely facilitates clonal hematopoiesis and contributes to the persistence of HLA(-) HSPCs in patients with AA.</p>

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Interferon-γ-mediated selective inhibition of hematopoiesis and the clonal advantage of HLA-lacking hematopoietic stem progenitor cells in aplastic anemia

  • 期刊论文

  • 发表日期：

    2025年4月11日

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  • Rio Takahashi,
  • Honoka Takahashi,
  • Luna Seoka,
  • Hiroka Iwasaki,
  • Hiroyuki Takamatsu,
  • Tatsuya Imi,
  • Yoshitaka Zaimoku,
  • Kohei Hosokawa,
  • Takamasa Katagiri

摘要

Acquired aplastic anemia (AA) is an immune-mediated bone marrow failure caused by autoreactive cytotoxic T lymphocytes targeting hematopoietic stem progenitor cells (HSPCs). Approximately 30% of AA patients exhibit leukocytes lacking HLA class I alleles (HLA[-]). In addition to this direct immune assault, the pathogenesis of AA is thought to involve indirect suppression mediated by the proinflammatory cytokine interferon-gamma (IFN-γ). Using HSPCs derived from induced pluripotent stem cells (iPSCs) with different HLA genotypes, HLA(-) HSPCs were found to be resistant to the suppressive effects of IFN-γ, whereas IFN-γ effectively suppressed the growth and development of HSPCs expressing HLA class I molecules. Further analysis showed that, in contrast to HLA(-) HSPCs, WT HSPCs showed enhanced CD119 expression in response to IFN-γ, activating downstream signaling pathways that promote apoptosis, suggesting that transcription factors involved in the apoptotic pathway following IFN-γ stimulation are differentially expressed between WT and HLA(-) HSPCs. Notably, IFN-γ stimulation reduced the expression of pSTAT3, a key regulator of apoptosis, in WT HSPCs, whereas its expression was elevated in HLA(-) HSPCs. In conclusion, this study showed that the selective hematopoietic inhibition of HSPCs by IFN-γ likely facilitates clonal hematopoiesis and contributes to the persistence of HLA(-) HSPCs in patients with AA.