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Id1 Transcription Inhibitor–Matrix Metalloproteinase 9 Axis Enhances Invasiveness of the Breakpoint Cluster Region/Abelson Tyrosine Kinase–Transformed Leukemia Cells

¹ Department of Microbiology and Immunology, School of Medicine, Temple University; ² Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and ³ Department of Clinical Cytobiology, Medical Center for Postgraduate Education, Warsaw, Poland

Requests for reprints: Tomasz Skorski, Department of Microbiology and Immunology, School of Medicine, Temple University, MRB, Room 548A, 3400 North Broad Street, Philadelphia, PA 19140. Phone: 215-707-9157; Fax: 215-707-9160; E-mail: tskorski{at}temple.edu.

Breakpoint cluster region/Abelson (BCR/ABL) tyrosine kinase enhances the ability of leukemia cells to infiltrate various organs. We show here that expression of the helix-loop-helix transcription factor Id1 is enhanced by BCR/ABL in a signal transducer and activator of transcription 5 (STAT5)–dependent manner. Enhanced expression of Id1 plays a key role in BCR/ABL–mediated cell invasion. Down-regulation of Id1 in BCR/ABL leukemia cells by the antisense cDNA significantly reduced their invasive capability through the Matrigel membrane and their ability to infiltrate hematopoietic and nonhematopoietic organs resulting in delayed leukemogenesis in mice. The Id1-promoted cell invasiveness was seemingly mediated by matrix metalloproteinase 9 (MMP9). Transactivation of MMP9 promoter in BCR/ABL cells was dependent on Id1 and abrogation of the MMP9 catalytic activity by a metalloproteinase inhibitor or blocking antibody decreased invasive capacity of leukemia cells. These data suggest that BCR/ABL-STAT5-Id1-MMP9 pathway may play a critical role in BCR/ABL–mediated leukemogenesis by enhancing invasiveness of leukemia cells. (Cancer Res 2006; 66(8): 4108-16)

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