Our hosting provider will be undergoing maintenance on Tuesday, August 30 between 8am and 5pm PDT. SciCrunch services may be offline during the maintenance.

Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

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

Authors

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

Journal

Blood

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