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p210^BCR-ABL inhibits SDF-1 Chemotactic Response via Alteration of CXCR4 Signaling and Down-regulation of CXCR4 Expression

Institut National de la Sante et de la Recherche Medicale, Institut Gustave Roussy, Villejuif, France

Requests for reprints: Fawzia Louache, Institut National de la Sante et de la Recherche Medicale U 362, Institut Gustave Roussy, PR1, 39 Rue Camille Desmoulins 94805 Villejuif, France. Phone: 33-1-42-11-42-33; Fax: 33-1-42-1152-40; E-mail: fawl{at}igr.fr.

It has been shown that p210^BCR-ABL significantly impairs CXCR4 signaling. We report here that the migratory response to SDF-1 was profoundly altered in blast crisis, whereas chronic-phase CD34⁺ cells migrated normally to this chemokine. This migratory defect was associated with a low CXCR4 membrane expression. In vitro STI-571 treatment of CD34⁺ cells from patients in blast crisis markedly increased the CXCR4 transcript and CXCR4 membrane expression. Because p210^BCR-ABL frequently increases with disease progression, we determined the effects of high and low p210^BCR-ABL expression on CXCR4 protein in the granulocyte macrophage colony-stimulating factor–dependent human cell line MO7e. p210^BCR-ABL expression distinctly alters CXCR4 protein through two different mechanisms depending on its expression level. At low expression, a signaling defect was detected with no modification of CXCR4 expression. However, higher p210^BCR-ABL expression induced a marked down-regulation of CXCR4 that is related to its decreased transcription. The effect of p210^BCR-ABL required its tyrosine kinase activity. Collectively, these data indicate that p210^BCR-ABL could affect CXCR4 by more than one mechanism and suggest that down-regulation of CXCR4 may have important implications in chronic myelogenous leukemia pathogenesis.

Key Words: BCR-ABL • CXCR4 • transcriptional regulation • CML • chemokines

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