Myeloid leukemias have increased activity of the nonhomologous end-joining pathway and concomitant DNA misrepair that is dependent on the Ku70/86 heterodimer

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Abstract

Human myeloid leukemias are characterized by chromosomal abnormalities, including translocations, deletions, and allelic loss. These alterations are known to disrupt the function of genes that contribute to tumor initiation and progression. The mechanism underlying the appearance of these chromosomal alterations is poorly understood. Recent evidence suggests that altered nonhomologous end joining (NHEJ) is associated with the incidence of chromosome abnormalities in mutant rodent cells. This pathway is thought to provide a major mechanism for the repair of double-strand breaks (DSB) in higher eukaryotes. Here, we show that in an in vitro assay for DSB end ligation, nuclear extracts prepared from cultured and primary myeloid leukemia cells show a 2-7-fold increase in end-ligation efficiency as compared with mobilized peripheral CD34+ blood progenitor cells (CD34+) and interleukin-2-stimulated peripheral blood lymphocytes from normal healthy donors (P <0.001). Furthermore, using an in vitro plasmid LacZ gene reactivation assay to determine DSB repair fidelity, nuclear extracts prepared from myeloid leukemia cells showed an increased frequency of misrepair compared with normal control cells (P <0.001). Most importantly, this misrepair in myeloid leukemia cells is associated with large deletions (30-400 bp) within the test plasmids used in our assay. These deletions were not observed using normal hematopoietic cells (
Original languageEnglish
Pages (from-to)2791 - 2797
Number of pages7
JournalCancer Research
Volume62
Issue number10
Publication statusPublished - 15 May 2002

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