The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl.
The bcr/abl fusion in chronic myelogenous leukemia (CML) creates a chimeric tyrosine kinase with dramatically different properties than intact c-abl. In P210 bcr/abl, the bcr portion includes a coiled-coil oligomerization domain (amino acids 1-63) and a grb2-binding site at tyrosine 177 (Tyr177) that are critical for fibroblast transformation, but give variable results in other cell lines. To investigate the role of the coiled-coil domain and Tyr177 in promoting CML, 4 P210 bcr/abl-derived mutants containing different bcr domains fused to abl were constructed. All 4 mutants, Delta(1-63) bcr/abl, (1-63) bcr/abl, Tyr177Phe bcr/abl, and (1-210) bcr/abl exhibited elevated tyrosine kinase activity and conferred factor-independent growth in cell lines. In contrast, differences in the transforming potential of the 4 mutants occurred in our mouse model, in which all mice receiving P210 bcr/abl-expressing bone marrow cells exclusively develop a myeloproliferative disease (MPD) resembling human CML. Of the 4 mutants assayed, only 1-210 bcr/abl, containing both the coiled-coil domain and Tyr177, induced MPD. Unlike full-length P210, this mutant also caused a simultaneous B-cell acute lymphocytic leukemia (ALL). The other 3 mutants, (1-63) bcr/abl, Tyr177Phe bcr/abl, and Delta(1-63) bcr/abl, failed to induce an MPD but instead caused T-cell ALL. These results show that both the bcr coiled-coil domain and Tyr177 are required for MPD induction by bcr/abl and provide the basis for investigating downstream signaling pathways that lead to CML.
Pubmed ID: 11929787 RIS Download
Animals | Base Sequence | Binding Sites | Bone Marrow Cells | Bone Marrow Transplantation | Cell Transformation, Neoplastic | Fusion Proteins, bcr-abl | Leukemia, Myelogenous, Chronic, BCR-ABL Positive | Mice | Models, Animal | Mutation | Neoplasms, Experimental | Oncogene Proteins | Peptide Fragments | Precursor Cell Lymphoblastic Leukemia-Lymphoma | Protein Structure, Tertiary | Protein-Tyrosine Kinases | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-bcr | Survival Analysis | Transduction, Genetic | Tumor Cells, Cultured | Tyrosine