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

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

doi:10.1038/s41375-025-02595-6

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

Leukemia. 2025 Apr 11. doi: 10.1038/s41375-025-02595-6. Online ahead of print.

Authors

Rio Takahashi¹, Honoka Takahashi¹, Luna Seoka¹, Hiroka Iwasaki¹, Hiroyuki Takamatsu^{2

3}, Tatsuya Imi², Yoshitaka Zaimoku², Kohei Hosokawa², Takamasa Katagiri⁴

Affiliations

¹ Department of Clinical Laboratory Science, Graduate School of Medical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa, 920-0942, Japan.
² Department of Hematology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
³ Faculty of Transdisciplinary Sciences for Innovation, Institute of Transdisciplinary Sciences for Innovation, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan.
⁴ Department of Clinical Laboratory Science, Graduate School of Medical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa, 920-0942, Japan. takama@staff.kanazawa-u.ac.jp.

PMID: 40217071
DOI: 10.1038/s41375-025-02595-6

Abstract

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.

Abstract

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