title: Paroxysmal nocturnal hemoglobinuria with copy number-neutral 6pLOH in GPI (+) but not in GPI (-) granulocytes.
abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired bone marrow disorder caused by expansion of a clone of hematopoietic cells lacking glycosylphosphatidylinositol (GPI)-anchored membrane proteins. Multiple lines of evidence suggest immune attack on normal hematopoietic stem cells provides a selective growth advantage to PNH clones. Recently, frequent loss of HLA alleles associated with copy number-neutral loss of heterozygosity in chromosome 6p (CN-6pLOH) in aplastic anemia (AA) patients was reported, suggesting that AA hematopoiesis 'escaped' from immune attack by loss of HLA alleles. We report here the first case of CN-6pLOH in a Japanese PNH patient only in GPI-anchored protein positive (59%) granulocytes, but not in GPI-anchored protein negative (41%) granulocytes. CN-6pLOH resulted in loss of the alleles A*02:06-DRB1*15:01-DQB1*06:02, which have been reported to be dominant in Japanese PNH patients. Our patient had maintained nearly normal blood count for several years. Our case supports the hypothesis that a hostile immune environment drives selection of resistant hematopoietic cell clones and indicates that clonal evolution may occur also in normal phenotype (non-PNH) cells in some cases.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Ueda
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Nishimura
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kajigaya
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kanakura
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
mesh_terms: D000328:Adult; D000483:Alleles; D002896:Chromosomes, Human, Pair 6; D002999:Clone Cells; D018628:Gene Dosage; D017261:Glycosylphosphatidylinositols / Q000737:chemistry / Q000172:deficiency*; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D059866:HLA-DQ beta-Chains / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D008297:Male
chemical_list: D017261:Glycosylphosphatidylinositols; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains
keywords: array comparative genomic hybridization; bone marrow failure syndromes; clonal evolution; loss of heterozygosity; paroxysmal nocturnal hemoglobinuria