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.
Bone Marrow ; DNA ; DNA Damage ; Fanconi Anemia ; Hematopoietic Stem Cells ; Leukemia ; Stem Cells

Twenty-one rabbits were randomly divided into three groups: experimental group-filling vein with two neural segments being 0.3cm long to bridge 4cm defect of common peroneal nerve, control group-bridging vein directly to the 4cm defect of common peroneal nerve, auto-nerve-grafting group-cutting off a segment (4cm long) from common peroneal nerve and grafting it inversely.After 25 weeks, morphological, electrophysiological and histological examinations were undertaken, which revealed that the experimental group was most similar to the auto-nerve-grafting group in recovery of motion of the limbs, action potential of muscle, nerve conductive velocity, and regenerating density of nerve fibers and axons. It was a failure in control group. Satisfactory results were also achieved in 2 patients with defect of ulnar nerve treated by filling vein with two neural segments. It suggests that our method is feasible.