Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia. | Aplastic Anemia and MDS International Foundation

Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia.

Journal Title: 
Blood
Author(s): 
Katagiri T, Sato-Otsubo A, Kashiwase K, Morishima S, Sato Y, Mori Y, Kato M, Sanada M, Morishima Y, Hosokawa K, Sasaki Y, Ohtake S, Ogawa S, Nakao S.
Primary Author: 
Katagiri T
Original Publication Date: 
Friday, September 30, 2011

Idiopathic aplastic anemia (AA) is a common cause of acquired bone marrow failure. Although autoimmunity to hematopoietic progenitors is thought to be responsible for its pathogenesis, little is known about the molecular basis of this autoimmunity. Here we show that a substantial proportion of AA patients harbors clonal hematopoiesis characterized by the presence of acquired copy number-neutral loss of heterozygosity (CNN-LOH) of the 6p arms (6pLOH). The 6pLOH commonly involved the human leukocyte antigen (HLA) locus, leading to loss of one HLA haplotype. Loss of HLA-A expression from multiple lineages of leukocytes was confirmed by flow cytometry in all 6pLOH(+) cases. Surprisingly, the missing HLA-alleles in 6pLOH(+) clones were conspicuously biased to particular alleles, including HLA-A*02:01, A*02:06, A*31:01, and B*40:02. A large scale epidemiological study on the HLA alleles of patients with various hematologic diseases revealed that the four HLA alleles were overrepresented in the germline of AA patients. These findings indicate that the 6pLOH(+) hematopoiesis found in AA represents 'escape' hematopoiesis from the autoimmunity, which is mediated by cytotoxic T-cells that target the relevant auto-antigens presented on hematopoietic progenitors through these class I HLAs. Our results provide a novel insight into the genetic basis of the pathogenesis of AA.

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