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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.

Publication ,  Journal Article
He, Y; Wertheim, JA; Xu, L; Miller, JP; Karnell, FG; Choi, JK; Ren, R; Pear, WS
Published in: Blood
April 15, 2002

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.

Duke Scholars

Published In

Blood

DOI

ISSN

0006-4971

Publication Date

April 15, 2002

Volume

99

Issue

8

Start / End Page

2957 / 2968

Location

United States

Related Subject Headings

  • Tyrosine
  • Tumor Cells, Cultured
  • Transduction, Genetic
  • Survival Analysis
  • Proto-Oncogene Proteins c-bcr
  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Protein Structure, Tertiary
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Peptide Fragments
 

Citation

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ICMJE
MLA
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He, Y., Wertheim, J. A., Xu, L., Miller, J. P., Karnell, F. G., Choi, J. K., … Pear, W. S. (2002). The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl. Blood, 99(8), 2957–2968. https://doi.org/10.1182/blood.v99.8.2957
He, Yiping, Jason A. Wertheim, Lanwei Xu, Juli P. Miller, Fredrick G. Karnell, John K. Choi, Ruibao Ren, and Warren S. Pear. “The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl.Blood 99, no. 8 (April 15, 2002): 2957–68. https://doi.org/10.1182/blood.v99.8.2957.
He Y, Wertheim JA, Xu L, Miller JP, Karnell FG, Choi JK, et al. The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl. Blood. 2002 Apr 15;99(8):2957–68.
He, Yiping, et al. “The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl.Blood, vol. 99, no. 8, Apr. 2002, pp. 2957–68. Pubmed, doi:10.1182/blood.v99.8.2957.
He Y, Wertheim JA, Xu L, Miller JP, Karnell FG, Choi JK, Ren R, Pear WS. The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl. Blood. 2002 Apr 15;99(8):2957–2968.

Published In

Blood

DOI

ISSN

0006-4971

Publication Date

April 15, 2002

Volume

99

Issue

8

Start / End Page

2957 / 2968

Location

United States

Related Subject Headings

  • Tyrosine
  • Tumor Cells, Cultured
  • Transduction, Genetic
  • Survival Analysis
  • Proto-Oncogene Proteins c-bcr
  • Proto-Oncogene Proteins
  • Protein-Tyrosine Kinases
  • Protein Structure, Tertiary
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Peptide Fragments