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Molecular and Cellular Biology, February 2001, p. 840-853, Vol. 21, No. 3
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.3.840-853.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The NH2-Terminal Coiled-Coil Domain and Tyrosine 177 Play Important Roles in Induction of a Myeloproliferative Disease in Mice by Bcr-Abl

Xiaowu Zhang,1,2 Ramesh Subrahmanyam,1,3 Ray Wong,1,3 Alec W. Gross,1,3 and Ruibao Ren1,3,*

Rosenstiel Basic Medical Sciences Research Center,1 Department of Biochemistry,2 and Department of Biology,3 Brandeis University, Waltham, Massachusetts 02454-9110

Received 17 July 2000/Returned for modification 1 September 2000/Accepted 13 November 2000

Bcr-Abl, a fusion protein generated by t(9;22)(q34;q11) translocation, plays a critical role in the pathogenesis of chronic myelogenous leukemia (CML). It has been shown that Bcr-Abl contains multiple functional domains and motifs and can disrupt regulation of many signaling pathways and cellular functions. However, the role of specific domains and motifs of Bcr-Abl or of specific signaling pathways in the complex in vivo pathogenesis of CML is not completely known. We have previously shown that expression of Bcr-Abl in bone marrow cells by retroviral transduction efficiently induces a myeloproliferative disorder (MPD) in mice resembling human CML. We have also shown that the Abl kinase activity within Bcr-Abl is essential for Bcr-Abl leukemogenesis, yet activation of the Abl kinase without Bcr sequences is not sufficient to induce MPD in mice. In this study we investigated the role of Bcr sequences within Bcr-Abl in inducing MPD using this murine model for CML. We found that the NH2-terminal coiled-coil (CC) domain was both essential and sufficient, even though not efficient, to activate Abl to induce an MPD in mice. Interestingly, deletion of the Src homology 3 domain complemented the deficiencies of the CC-deleted Bcr-Abl in inducing MPD in mice. We further demonstrated that the Grb2 binding site at Y177 played an important role in efficient induction of MPD. These studies directly demonstrated the important roles of Bcr sequences in induction of MPD by Bcr-Abl.

* Corresponding author. Mailing address: Rosenstiel Basic Medical Sciences Research Center, MS 029, Brandeis University, 415 South Street, Waltham, MA 02454-9110. Phone: (781) 736-2486. Fax: (781) 736-2405. E-mail: ren{at}hydra.rose.brandeis.edu.

Molecular and Cellular Biology, February 2001, p. 840-853, Vol. 21, No. 3
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.3.840-853.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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