Genetic Mutations Driving Aplastic Anemia: A Focus on Key Allelic Changes

Aplastic Anemia (AA) is a rare blood disorder where the bone marrow fails, leading to pancytopenia. Most of the time it is idiopathic; however, it can also be caused by drugs, radiation, infections, or genetic issues. Recent molecular research has revealed that specific mutations in the Human Leukocyte Antigen (HLA) genes play a pivotal role in AA's pathogenesis, clinical presentation, and therapeutic response. Notably, mutations in the HLA have emerged as crucial in the disease's molecular pathway. These mutations interfere with HLA coding. Specifically, cytotoxic CD8+ T cells become aberrantly activated and undergo clonal expansion that continues to attack the hematopoietic stem cells (HSCs). Advances in genetic screening allow the detection of these specific mutations, enabling a more personalized treatment approach, considering immunosuppressive therapies (IST) or bone marrow transplantation. This review is based on the role of the most common HLA genotype (HLA-B*40:02 and HLA-B*14:02) and somatic mutations (TERT, TERC, ASXL1, and DNMT3A) in contributing to immune dysregulation and the clinical presentation of AA according to the severity, treatment response, and prognosis depending on the mutation presented.