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Prepublished online as a Blood First Edition Paper on February 6, 2003; DOI 10.1182/blood-2002-10-3011.
Submitted October 7, 2002
Accepted January 24, 2003
Downregulation of BRCA-1 in BCR-ABL-expressing hematopoietic cells
Eric Deutsch, Sylvie Jarrousse, Dorothee Buet, Aymeric Dugray, Marie-Laure Bonnet, Marie-Catherine Vozenin-Brotons, Francois Guilhot, Ali G Turhan, Jean Feunteun, and Jean Bourhis*
Translational Research-Cell Therapy Laboratory, Department of Clinical Biology, Val de Marne, Gustave Roussy Institute, Villejuif, France
Departement d'Onco-Hematologie, Poitiers, France
* Corresponding author; email: bourhis{at}igr.fr.
BCR-ABL fusion oncogene is the molecular hallmark of chronic myelogenous leukemia (CML) a condition characterized by a progression from a chronic to an acute phase leukemia due to secondary genetic events the nature of which remains largely unknown. Here we report that the expression of the P210 BCR-ABL fusion protein leads to a downregulation of BRCA1 protein, a gene product involved in the maintenance of genome integrity. BRCA1 protein is nearly undetectable in leukemia cells from CML patients, both during the chronic phase and in blast crisis. Similarly, stable transfection-enforced expression of p210 protein in established hemopoietic cell lines leads to severe BRCA1 depletion. The lack of significant change in BRCA1 mRNA level in cells expressing p210 supports the hypothesis that the regulation of BRCA1 protein level occurs post-transcriptionally. It is abolished upon exposure of the cells to STI571 and by mutation in the ATP pocket of p210 and thus seems to require the tyrosine kinase activity of BCR-ABL. Cell lines expressing high level of BCR-ABL, display an increased rate of sister-chromatid-exchange and chromosome aberrations after ionizing radiation. These findings reveal a novel link between the oncoprotein BCR-ABL and the tumor-suppressor protein BRCA1.
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