title: Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH).
abstract: Somatic mutation of PIGA in hematopoietic stem cells causes deficiency of glycosyl phosphatidylinositol-anchored proteins in paroxysmal nocturnal hemoglobinuria (PNH) that underlies the intravascular hemolysis but does not account for expansion of the PNH clone. Immune mechanisms may mediate clonal selection but appear insufficient to account for the clonal dominance necessary for PNH to become clinically apparent. Herein, we report 2 patients with PNH whose PIGA-mutant cells had a concurrent, acquired rearrangement of chromosome 12. In both cases, der(12) had a break within the 3' untranslated region of HMGA2, the architectural transcription factor gene deregulated in many benign mesenchymal tumors, that caused ectopic expression of HMGA2 in the bone marrow. These observations suggest that aberrant HMGA2 expression, in concert with mutant PIGA, accounts for clonal hematopoiesis in these 2 patients and suggest the concept of PNH as a benign tumor of the bone marrow.
authors.affiliation: Department of Molecular Genetics, Osaka Medical Center for Cancer, Japan.
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Inoue
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Izui-Sarumaru
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Endo
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Nishimura
authors.forename: Ken
authors.initials: K
authors.lastname: Kurokawa
authors.forename: Maki
authors.initials: M
authors.lastname: Kuwayama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shime
authors.forename: Takashi
authors.initials: T
authors.lastname: Machii
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kanakura
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Meyers
authors.forename: Carl
authors.initials: C
authors.lastname: Wittwer
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: William
authors.initials: W
authors.lastname: Babcock
authors.forename: Debra
authors.initials: D
authors.lastname: Frei-Lahr
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Parker
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics*; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006461:Hemolysis / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein