Mechanisms of transformation by the BCR-ABL oncogene: new perspectives in the post-imatinib era
Section snippets
The sensitivity of Abl to imatinib is dictated by the regulatory conformation of the enzyme
To appreciate the dynamics of inhibition of Abl by imatinib it is necessary to understand the regulatory mechanisms governing the catalytic activity of the different forms of the enzyme. It is instructive to consider first the normal c-Abl protein, which has two isoforms (types Ia and Ib) that result from expression of two small alternative first exons. Type Ib c-Abl contains a C14 myristoyl fatty acid moiety covalently linked to the N-terminus and is expressed at higher levels than type Ia,
Mechanism of dysregulation of Abl by fusion of Bcr
While the catalytic activity of c-Abl is tightly controlled within the cell, the Bcr-Abl fusion protein has constitutively high tyrosine kinase activity in vivo and in vitro compared to c-Abl [15]. However, the exact mechanism of dysregulation of Abl kinase activity upon fusion with Bcr has remained unclear despite nearly two decades of intensive research. Relative to c-Abl, the Bcr-Abl fusion protein retains the Abl SH3 domain but lacks Abl first exon sequences and myristoylation and has
The imatinib-sensitive state of Bcr-Abl is monomeric, unphosphorylated, and autoinhibited via the SH3 domain
A recent study has clarified the mechanism of Bcr-Abl regulation by demonstrating that the fusion protein, like c-Abl, is negatively regulated through its SH3 domain [25]. Substitution of alanine for the hydrophobic amino acids at the “a” and “d” positions across the Bcr coiled-coil domain abolishes oligomerization of Bcr-Abl in vivo, and greatly impairs kinase activity in vivo as assessed by phosphotyrosine levels. The low but detectable in vivo tyrosine kinase of monomeric Bcr-Abl may reflect
Bcr-Abl activates many signaling pathways in cell lines, but not all are likely to be relevant to leukemogenesis
Since its discovery over 15 years ago, Bcr-Abl has been intensively studied in cell lines, including human Ph+ cell lines such as K562, and other hematopoietic and non-hematopoietic (e.g. fibroblast) cell lines into which the BCR-ABL gene has been transferred. Because Bcr-Abl is a constitutively active tyrosine kinase, expression of this fusion protein causes activation of a myriad of signaling pathways within the cell, and this has been the subject of several recent and comprehensive reviews
The Grb2–Gab2 connection: an essential signaling pathway downstream of Bcr Tyr177
A good example of the importance of animal models in identifying and validating molecular targets for therapy of CML downstream of Bcr-Abl is the pathway emanating from Tyr177. This residue is highly tyrosine phosphorylated in the active form of Bcr-Abl as a consequence of autophosphorylation and possibly via trans-phosphorylation by Src kinases such as Fps [51]. Phosphorylated Tyr177 forms a high-affinity binding site for the SH2 domain of the adapter protein Grb2 [52], [53]. Mutation of
Summary
The past several years have been marked by extraordinarily rapid progress in the biology and treatment of CML. Imatinib is now the paradigm for molecularly targeted cancer therapy. In reality, imatinib and similar drugs are both therapeutic agents and valuable tools for understanding the molecular pathogenesis of CML. The challenge for the future is to improve upon current clinical results with kinase inhibitor therapy in CML and develop treatment strategies that result in eradication and cure
Acknowledgements
This work was supported by NIH grant CA90576 and a SCOR grant from the Leukemia and Lymphoma Society. The author is a Stohlman Scholar of the Leukemia and Lymphoma Society.
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