Identification of high-frequency genes in non-severe aplastic anemia and their impact on therapeutic response

Non-severe aplastic anemia (NSAA) is a hematopoietic disorder characterized by variable treatment responses. However, the relationship between hematopoietic clonal mutations harbored by NSAA patients and their treatment outcomes and prognosis remains unclear. In this study, whole-exome sequencing was performed to analyze the genetic landscape of 87 patients with NSAA, identifying high-frequency mutations in CSMD1 , PIGA , FAT1 , and BCOR/L1 ( BCOR and its homolog BCORL1 ). Missense mutations were predominant, particularly in transfusion-dependent NSAA. Gene ontology analysis of the genes in nonresponding patients revealed enrichment in the pathways related to protein, ATP, and metal ion binding. Patients with PIGA mutations showed significantly better treatment responses, whereas those with FAT1 mutations exhibited poorer outcomes. Notably, bone marrow failure-related germline mutations were linked to reduced responses to immunosuppressive therapy, particularly those coexisting with somatic BCOR/L1 mutations. Although previous studies have suggested a favorable prognosis in BCOR/L1 -mutated AA patients, our survival analysis revealed a paradox: BCOR/L1 mutations in patients harboring coexisting bone marrow failure-related germline mutations were associated with inferior event-free survival, similar to FAT1 mutations. This discrepancy may reflect distinct mutation subtypes or epistatic interactions between germline predisposition and somatic lesions. Overall, this study provides insights that may help optimize personalized treatment for patients strategies with NSAA.