Bone marrow (BM) failure is a condition characterized by peripheral pancytopenia due to decreased BM function. It includes conditions such as acquired aplastic anemia (AA), myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria (PNH). AA is characterized by pancytopenia and BM hypoplasia, and is primarily caused by an autoimmune mechanism involving cytotoxic T cells that damage hematopoietic stem cells (HSCs). Recent genomic research has revealed that patients with AA often exhibit clonal hematopoiesis by HSCs with genetic alterations, such as PIGA, DNMT3A, ASXL1, BCOR/BCORL1, copy-number neutral LOH of chromosome 6p (6pLOH), and HLA class I allele mutations. The genomic landscape of AA is distinct from MDS and age-related clonal hematopoiesis. Most notably, the presence of PNH-type cells and HLA class I allele-lacking cells indicates the presence of HSCs that have escaped from autoimmunity. We recently identified a common nonsense mutation at codon19 (c.19C>T, p.R7X) in exon1 (Exon1mut) of different HLA-A and HLA-B alleles, and HLA-DR loss of hematopoietic stem progenitor cells in AA patients carrying HLA-DR15. These results provide important clues for understanding the immune pathophysiology of BM failure.
Keywords: Aplastic anemia; Bone marrow failure; Escape hematopoiesis; HLA-DR15.