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Blood, 1 April 2001, Vol. 97, No. 7, pp. 2084-2090
NEOPLASIA
BCR-ABL down-regulates the DNA repair protein DNA-PKcs
Eric Deutsch,
Aymeric Dugray,
Bassam AbdulKarim,
Elisabetta Marangoni,
Laurence Maggiorella,
Sabine Vaganay,
Radia M'Kacher,
Setha Douc Rasy,
François Eschwege,
William Vainchenker,
Ali G. Turhan, and
Jean Bourhis
From the UPRES EA 27-10 Radiosensibilité-Radiocarcinogenèse Humaine and METSI;
INSERM U 362 and Translational Research Laboratory, Institut Gustave
Roussy, Villejuif, France.
This study demonstrates in both stable and inducible
BCR-ABL-expressing hematopoietic cells a down-regulation of the major mammalian DNA repair protein DNA-PKcs by BCR-ABL. Similar results were
found in BCR-ABL CD34+ cells from patients with chronic
myelogenous leukemia (CML). DNA-PKcs down-regulation is a
proteasome-dependent degradation that requires tyrosine kinase activity
and is associated with a marked DNA repair deficiency along with
increased sensitivity to ionizing radiation. The conjunction of a major
DNA repair deficiency and a resistance to apoptosis, both induced by
BCR-ABL, provides a new mechanism to explain how secondary genetic
alterations can accumulate in CML, eventually leading to blast crisis.
The down-regulation of DNA-PKcs was reversible in CD34+ CML
cells suggesting that this approach might offer a novel and powerful
therapeutic strategy in this disease, especially to delay the blast crisis.
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