title: Reversibility of Defective Hematopoiesis Caused by Telomere Shortening in Telomerase Knockout Mice.
abstract: Telomere shortening is common in bone marrow failure syndromes such as dyskeratosis congenita (DC), aplastic anemia (AA) and myelodysplastic syndromes (MDS). However, improved knowledge of the lineage-specific consequences of telomere erosion and restoration of telomere length in hematopoietic progenitors is required to advance therapeutic approaches. We have employed a reversible murine model of telomerase deficiency to compare the dependence of erythroid and myeloid lineage differentiation on telomerase activity. Fifth generation Tert-/- (G5 Tert-/-) mice with shortened telomeres have significant anemia, decreased erythroblasts and reduced hematopoietic stem cell (HSC) populations associated with neutrophilia and increased myelopoiesis. Intracellular multiparameter analysis by mass cytometry showed significantly reduced cell proliferation and increased sensitivity to activation of DNA damage checkpoints in erythroid progenitors and in erythroid-biased CD150hi HSC, but not in myeloid progenitors. Strikingly, Cre-inducible reactivation of telomerase activity restored hematopoietic stem and progenitor cell (HSPC) proliferation, normalized the DNA damage response, and improved red cell production and hemoglobin levels. These data establish a direct link between the loss of TERT activity, telomere shortening and defective erythropoiesis and suggest that novel strategies to restore telomerase function may have an important role in the treatment of the resulting anemia.
authors.affiliation: Stanford Cancer Institute and Division of Hematology, Department of Medicine, Stanford University, Stanford, CA, 94305, United States of America.
authors.forename: Aparna
authors.initials: A
authors.lastname: Raval
authors.affiliation: Stanford Cancer Institute and Division of Hematology, Department of Medicine, Stanford University, Stanford, CA, 94305, United States of America; Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology Stanford University, School of Medicine, Stanford, CA, 94305, United States of America.
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Behbehani
authors.affiliation: Stanford Cancer Institute and Division of Hematology, Department of Medicine, Stanford University, Stanford, CA, 94305, United States of America.
authors.forename: Le Xuan Truong
authors.initials: le XT
authors.lastname: Nguyen
authors.affiliation: Stanford Cancer Institute and Division of Hematology, Department of Medicine, Stanford University, Stanford, CA, 94305, United States of America; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94035, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Stanford Cancer Institute and Division of Hematology, Department of Medicine, Stanford University, Stanford, CA, 94305, United States of America.
authors.forename: Brenda
authors.initials: B
authors.lastname: Kusler
authors.affiliation: Department of Genetics, Stanford University, Stanford, CA, 94305, United States of America.
authors.forename: Alina
authors.initials: A
authors.lastname: Garbuzov
authors.affiliation: Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology Stanford University, School of Medicine, Stanford, CA, 94305, United States of America; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94035, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Ramunas
authors.affiliation: Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology Stanford University, School of Medicine, Stanford, CA, 94305, United States of America; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94035, United States of America.
authors.forename: Colin
authors.initials: C
authors.lastname: Holbrook
authors.affiliation: Human Oncology and Pathogenesis Program and Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, United States of America.
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.affiliation: Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology Stanford University, School of Medicine, Stanford, CA, 94305, United States of America; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94035, United States of America.
authors.forename: Helen
authors.initials: H
authors.lastname: Blau
authors.affiliation: Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology Stanford University, School of Medicine, Stanford, CA, 94305, United States of America.
authors.forename: Garry P
authors.initials: GP
authors.lastname: Nolan
authors.affiliation: Departments of Medicine and Biochemistry, Stanford University, Stanford, CA, 94305, United States of America.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Artandi
authors.affiliation: Stanford Cancer Institute and Division of Hematology, Department of Medicine, Stanford University, Stanford, CA, 94305, United States of America.
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Mitchell
mesh_terms: D000741:Anemia, Aplastic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D004249:DNA Damage; D015672:Erythroid Precursor Cells / Q000378:metabolism*; D006410:Hematopoiesis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere; D059506:Telomere Shortening / Q000235:genetics*
chemical_list: D019098:Telomerase