Essential roles for Pot1b in HSC self-renewal and survival

Blood. 2011 Dec 1;118(23):6068-77. doi: 10.1182/blood-2011-06-361527. Epub 2011 Sep 23.

Abstract

Maintenance of mammalian telomeres requires both the enzyme telomerase and shelterin, which protect telomeres from inappropriately activating DNA damage response checkpoints. Dyskeratosis congenita is an inherited BM failure syndrome disorder because of defects in telomere maintenance. We have previously shown that deletion of the shelterin component Pot1b in the setting of telomerase haploinsufficiency results in rapid telomere shortening and fatal BM failure in mice, eliciting phenotypes that strongly resemble human syskeratosis congenita. However, it was unclear why BM failure occurred in the setting of Pot1b deletion. In this study, we show that Pot1b plays an essential role in HSC survival. Deletion of Pot1b results in increased apoptosis, leading to severe depletion of the HSC reserve. BM from Pot1b(Δ/Δ) mice cannot compete with BM from wild-type mice to provide multilineage reconstitution, indicating that there is an intrinsic requirement for Pot1b the maintenance of HSC function in vivo. Elimination of the p53-dependent apoptotic function increased HSC survival and significantly extended the lifespan of Pot1b-null mice deficient in telomerase function. Our results document for the first time the essential role of a component of the shelterin complex in the maintenance of HSC and progenitor cell survival.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Anemia, Aplastic
  • Animals
  • Apoptosis / physiology
  • Bone Marrow Cells / cytology*
  • Bone Marrow Cells / physiology*
  • Bone Marrow Diseases
  • Bone Marrow Failure Disorders
  • Cell Differentiation / physiology
  • Cell Survival / physiology
  • Cells, Cultured
  • Chromosomes, Mammalian / genetics
  • DNA Damage / physiology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Female
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / physiology
  • Hemoglobinuria, Paroxysmal* / genetics
  • Hemoglobinuria, Paroxysmal* / pathology
  • Hemoglobinuria, Paroxysmal* / physiopathology
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Mutant Strains
  • Mice, SCID
  • Telomere / genetics*
  • Tumor Suppressor Protein p53 / genetics

Substances

  • DNA-Binding Proteins
  • POT1b protein, mouse
  • Tumor Suppressor Protein p53