Int J Stem Cells.  2019 Nov;12(3):457-462. 10.15283/ijsc19074.

Inactivation of the NHEJ Activity of DNA-PKcs Prevents Fanconi Anemia Pre-Leukemic HSC Expansion

Affiliations
  • 1Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. Qishen.pang@cchmc.org
  • 2Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Abstract

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure and high risk of cancer particularly leukemia. Here we show that inactivation of the non-homologous end-joining (NHEJ) activity of DNA-PKcs prevented DNA damage-induced expansion of FA pre-leukemic hematopoietic stem cells (HSCs). Furthermore, we performed serial BM transplantation to demonstrate that the DNA damage-induced expanded FA HSC compartment contained pre-leukemic stem cells that required the NHEJ activity of DNA-PKcs to induce leukemia in the secondary recipients. These results suggest that NHEJ may collaborate with FA deficiency to promote DNA damage-induced expansion of pre-leukemic HSCs.

Keyword

DNA damage; Fanconi anemia; Leukemic stem cells; Non-homologous end-joining

MeSH Terms

Bone Marrow
DNA
DNA Damage
Fanconi Anemia*
Hematopoietic Stem Cells
Leukemia
Stem Cells
DNA
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