Sustained clonal hematopoiesis by HLA-lacking hematopoietic stem cells without driver mutations in aplastic anemia

Abstract

Key Points HSPCs that lack HLA class I alleles can sustain clonal hematopoiesis without driver mutations or telomere attrition in AA patients. 6pLOH may confer a survival advantage to HSPCs with age-related somatic mutations, leading to the clonal expansion of mutant HSPCs.

Aplastic Anemia

“…Aplastic anemia is associated with specific histocompatibility antigens 2627 . More striking is the presence of “escape clones”, granulocytes with loss of the region of chromosome 6 that encompasses HLA alleles, in 10–15% of patients 2829,30 ; cells selected by absence of HLA, acquired by 6pLOH or somatic mutations, sustain hematopoiesis by clonal expansion 31 Immune escape has been hypothesized to explain clonal expansion of cells globally deficient in glycosylphosphoinositiol (GPI)-anchored proteins 32 in PNH, due to an acquired mutation in PIG-A in a stem cell. The GPI anchor itself has been suggested to be a target of the immune response.…”

Acquired Aplastic Anemia as a Clonal Disorder of Hematopoietic Stem Cells

“…Conversely, in two meta-analyses the impact of the role of granulocyte colony-stimulating factor in immunosuppressive therapy of AA on clonal evolution has not been determined [45,46]. Recently, data show that 6p-CN-LOH may confer a survival advantage to hematopoietic stem progenitor cells clones (HSPCs) with age-related somatic mutations, leading to the clonal expansion of mutant HSPCs [47].…”

“…Imi et al reported that in AA patients, hematopoietic stem progenitor cells (HSPCs) clones lacking an HLA class I allele which escape the cytotoxic T lymphocyte (CTL) attack are essentially free from somatic mutations related to myeloid malignancies and are able to support long-term clonal hematopoiesis without developing driver mutations in AA patients unless HLA loss occurs in HSPCs with somatic mutations [47].…”

Idiopathic Aplastic Anemia: An Update

“…In acquired aplastic anemia some Human Leukocyte Antigen System (HLA) (I and II) haplotypes, such as HLA-DR15, are over-represented [ 16 , 17 ]. These patients usually do better with immunosuppressive treatment.…”