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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


  • He Y
  • Wertheim JA
  • Xu L
  • Miller JP
  • Karnell FG
  • Choi JK
  • Ren R
  • Pear WS



Publication Data

April 15, 2002

Associated Grants

  • Agency: PHS HHS, Id: R01

Mesh Terms

  • 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