title: Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia.
abstract: The pathophysiology of severe aplastic anemia (SAA) is immune-mediated destruction of hematopoietic stem and progenitor cells (HSPCs). Most patients respond to immunosuppressive therapies, but a minority transform to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), frequently associated with monosomy 7 (-7). Thirteen SAA patients were analyzed for acquired mutations in myeloid cells at the time of evolution to -7, and all had a dominant HSPC clone bearing specific acquired mutations. However, mutations in genes associated with MDS/AML were present in only 4 cases. Patients who evolved to MDS and AML showed marked progressive telomere attrition before the emergence of -7. Single telomere length analysis confirmed accumulation of short telomere fragments of individual chromosomes. Our results indicate that accelerated telomere attrition in the setting of a decreased HSPC pool is characteristic of early myeloid oncogenesis, specifically chromosome 7 loss, in MDS/AML after SAA, and provides a possible mechanism for development of aneuploidy.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Bogdan
authors.initials: B
authors.lastname: Dumitriu
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Xingmin
authors.initials: X
authors.lastname: Feng
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Townsley
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan;
authors.forename: Tetsuichi
authors.initials: T
authors.lastname: Yoshizato
authors.affiliation: Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, SP, Brazil; and.
authors.forename: Rodrigo T
authors.initials: RT
authors.lastname: Calado
authors.affiliation: DNA Sequencing and Computational Biology Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: DNA Sequencing and Computational Biology Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Wakabayashi
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kajigaya
authors.affiliation: Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan;
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: DNA Sequencing and Computational Biology Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
mesh_terms: D000741:Anemia, Aplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059505:Telomere Homeostasis