Id1 transcription inhibitor-matrix metalloproteinase 9 axis enhances invasiveness of the breakpoint cluster region/abelson tyrosine kinase-transformed leukemia cells.
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.
Nieborowska-Skorska
Margaret
M
Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, USA.
Hoser
Grazyna
G
Rink
Lori
L
Malecki
Maciej
M
Kossev
Plamen
P
Wasik
Mariusz A
MA
Skorski
Tomasz
T
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology; D051798:Inhibitor of Differentiation Protein 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation
C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D050799:STAT5 Transcription Factor; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D020780:Matrix Metalloproteinase 9