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

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.

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.

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.

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.