The role of Lyn kinase in the development of imatinib resistance in chronic myelogenous leukemia
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EDITORIAL
The role of Lyn kinase in the development of imatinib resistance in chronic myelogenous leukemia
Camillo Porta • Federica Tagliani Published online: 11 July 2008 ©Springer-Verlag 2008
C. Porta (Y) Medical Oncology and Laboratory of Pre-clinical Oncology and Experimental Therapies IRCCS San Matteo University Hospital Foundation, Pavia, Italy e-mail: [email protected] F. Tagliani Laboratory of Pre-Clinical Oncology and Developmental Therapeutics, IRCCS San Matteo University Hospital Foundation, Pavia, Italy
Imatinib mesylate, a small-molecule inhibitor of BCRABL tyrosine kinase activity, has emerged as the well-recognized standard of treatment for chronic myelogenous leukemia (CML). Indeed, both its efficacy, tolerability, as well as cost-effectiveness have been clearly proven [1]. Despite imatinib's activity, the development of resistance, whether BCR-ABL dependent or independent, is of great concern and is ultimately responsible for disease progression [2, 3]. BCR-ABL-dependent resistance is commonly a result of mutations in the BCR-ABL gene, which can induce a structural shift of the BCR-ABL protein, from inactive conformation, which imatinib binds, to active conformation, which imatinib is unable to bind. BCR-ABL gene amplification may also play a role in the development of imatinib resistance in patients with CML. However, the above mechanisms account for some but not all cases of imatinib resistance [3]. Indeed, a number of other BCR-ABL-independent mechanisms of imatinib resistance have been postulated, related to the expression/activation of other proteins. Besides the expression of the efflux protein multidrug resistance protein-1 [4], of which imatinib is a substrate, the Src family tyrosine kinases Lyn and Hck have been frequently implicated in imatinib resistance of CML [3, 5]. In a study that has been recently released online ahead of publication in the Journal of the National Cancer Institute, Wu and co-workers from the MD Anderson Cancer Center demonstrated that the persistent activation of the Lyn protein kinase may be one of the main factors involved in imatinib resistance [6]. Lyn is one of several Src-family tyrosine kinases [7], well-known for its ability to negatively regulate signaling pathways through phosphorylation of inhibitory receptors, enzymes, and adaptors. It is also a key mediator in several pathways of B-cell activation, such as CD19 and CD180.
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The importance of regulating Lyn activity is exemplified by the pathological conditions that develop in both Lyn-/and Lyn gain-of-function mice (Lynup/up), including lethal antibody-mediated autoimmune diseases and, notably, myeloid neoplasia [8]. The investigators tested both established, BCR-ABLmutation-negative CML cell lines and patients with BCRABL-mutation-negative CML. In patients and cells sensitive to imatinib treatment, the drug suppressed the overactivation of Lyn kinase; however, in imatinib-resistant cells and patients, Lyn kinase remained activated after imatinib treatment. When Lyn kinase activity was re
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