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Purpose <p>Bone marrow failure (BMF) in idiopathic aplastic anemia (AA) and hypoplastic myelodysplastic neoplasms (MDS-h) results from the destruction of hematopoietic progenitors by autoreactive T cells; however, the molecular events driving the pathogenesis of these disorders remain unclear. We therefore applied whole-exome sequencing (WES) in AA and MDS-h patients to identify acquired and inherited gene variants presumed to have functional consequences for BMF. We also used transcriptome profiling to investigate the molecular mechanisms underlying the aberrant T cell response.</p> Methods <p>WES was performed on DNA from 42 patients at diagnosis. Transcriptome profiling of CD3⁺ cells was conducted in 21 patients and 10 healthy donors. Peripheral blood cell populations were analyzed by flow cytometry.</p> Results <p>Pathogenic/likely pathogenic (P/LP) somatic gene variants were detected in 79% of patients and were functionally associated with BMF-relevant processes such as antigen processing/presentation, T cell-mediated immunity, and DNA repair. P/LP germline gene variants were found in all patients, almost half of whom harbored variants associated with inborn errors of immunity. Patient T cells displayed expression signatures of increased inflammation, apoptosis, hypoxia response, and decreased oxidative phosphorylation. Dysregulated long noncoding RNAs were predicted to primarily regulate the differentiation of T helper 17 cells. Patients also showed significantly lower frequencies of immature progenitors and natural killer cells compared with controls.</p> Conclusion <p>Patients with idiopathic AA and MDS-h carried multiple germline immune-related gene variants that may increase susceptibility to immune-mediated BMF. Furthermore, patient T cells exhibited altered energy metabolism, which may represent a therapeutic target for modulating immune responses in autoimmune diseases.</p>

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Overrepresentation of Germline Immune-Related Gene Variants in Patients with Acquired Bone Marrow Failure

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月5日

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  • Zuzana Pinc,
  • David Kundrat,
  • Monika Kaisrlikova,
  • Andrea Hrustincova,
  • Sarka Vanikova,
  • Iva Trsova,
  • Jitka Vesela,
  • Martin Vostry,
  • Barbora Pejsova,
  • Sarka Ransdorfova,
  • Lucie Slamova,
  • Tomas Prochazka,
  • Daniel Lysak,
  • Anna Jonasova,
  • Marketa Stastna Markova,
  • Jaroslav Cermak,
  • Monika Belickova,
  • Hana Votavova

摘要

Purpose

Bone marrow failure (BMF) in idiopathic aplastic anemia (AA) and hypoplastic myelodysplastic neoplasms (MDS-h) results from the destruction of hematopoietic progenitors by autoreactive T cells; however, the molecular events driving the pathogenesis of these disorders remain unclear. We therefore applied whole-exome sequencing (WES) in AA and MDS-h patients to identify acquired and inherited gene variants presumed to have functional consequences for BMF. We also used transcriptome profiling to investigate the molecular mechanisms underlying the aberrant T cell response.

Methods

WES was performed on DNA from 42 patients at diagnosis. Transcriptome profiling of CD3⁺ cells was conducted in 21 patients and 10 healthy donors. Peripheral blood cell populations were analyzed by flow cytometry.

Results

Pathogenic/likely pathogenic (P/LP) somatic gene variants were detected in 79% of patients and were functionally associated with BMF-relevant processes such as antigen processing/presentation, T cell-mediated immunity, and DNA repair. P/LP germline gene variants were found in all patients, almost half of whom harbored variants associated with inborn errors of immunity. Patient T cells displayed expression signatures of increased inflammation, apoptosis, hypoxia response, and decreased oxidative phosphorylation. Dysregulated long noncoding RNAs were predicted to primarily regulate the differentiation of T helper 17 cells. Patients also showed significantly lower frequencies of immature progenitors and natural killer cells compared with controls.

Conclusion

Patients with idiopathic AA and MDS-h carried multiple germline immune-related gene variants that may increase susceptibility to immune-mediated BMF. Furthermore, patient T cells exhibited altered energy metabolism, which may represent a therapeutic target for modulating immune responses in autoimmune diseases.