p53 Mediates Failure of Human Definitive Hematopoiesis in Dyskeratosis Congenita

Stem Cell Reports. 2017 Aug 8;9(2):409-418. doi: 10.1016/j.stemcr.2017.06.015. Epub 2017 Jul 27.


Dyskeratosis congenita (DC) is a bone marrow failure syndrome associated with telomere dysfunction. The progression and molecular determinants of hematopoietic failure in DC remain poorly understood. Here, we use the directed differentiation of human embryonic stem cells harboring clinically relevant mutations in telomerase to understand the consequences of DC-associated mutations on the primitive and definitive hematopoietic programs. Interestingly, telomere shortening does not broadly impair hematopoiesis, as primitive hematopoiesis is not impaired in DC cells. In contrast, while phenotypic definitive hemogenic endothelium is specified, the endothelial-to-hematopoietic transition is impaired in cells with shortened telomeres. This failure is caused by DNA damage accrual and is mediated by p53 stabilization. These observations indicate that detrimental effects of telomere shortening in the hematopoietic system are specific to the definitive hematopoietic lineages. This work illustrates how telomere dysfunction impairs hematopoietic development and creates a robust platform for therapeutic discovery for treatment of DC patients.

Keywords: bone marrow failure; disease modeling; dyskeratosis congenita; embryonic stem cells; hematopoiesis; telomerase; telomere damage; telomeres.

MeSH terms

  • Anemia, Aplastic / blood
  • Anemia, Aplastic / etiology
  • Anemia, Aplastic / pathology
  • Biomarkers
  • Bone Marrow / pathology
  • Bone Marrow Diseases / blood
  • Bone Marrow Diseases / etiology
  • Bone Marrow Diseases / pathology
  • Bone Marrow Failure Disorders
  • Cell Differentiation / genetics
  • DNA Damage
  • DNA Mutational Analysis
  • Dyskeratosis Congenita / blood*
  • Dyskeratosis Congenita / genetics*
  • Dyskeratosis Congenita / pathology
  • Embryonic Stem Cells / metabolism
  • Gene Knockout Techniques
  • Gene Targeting
  • Hematopoiesis / genetics*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism
  • Hemoglobinuria, Paroxysmal / blood
  • Hemoglobinuria, Paroxysmal / etiology
  • Hemoglobinuria, Paroxysmal / pathology
  • Histones / metabolism
  • Humans
  • Immunophenotyping
  • Models, Biological
  • Mutation
  • Phenotype
  • Telomere
  • Telomere Homeostasis / genetics
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism


  • Biomarkers
  • Histones
  • Tumor Suppressor Protein p53

Supplementary concepts

  • Bone Marrow failure syndromes