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 Blood, 1 April 2008, Vol. 111, No. 7, pp. 3821-3829.
Prepublished online as a Blood First Edition Paper on January 30, 2008; DOI 10.1182/blood-2007-08-109330.

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NEOPLASIA

Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells

Ji Wu1, Feng Meng1, Henry Lu2, Ling Kong1, William Bornmann3, Zhenghong Peng3, Moshe Talpaz2, and Nicholas J. Donato2

1 Department of Experimental Therapeutics, The University of Texas, M. D. Anderson Cancer Center, Houston, TX; 2 Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; and 3 Department of Experimental Diagnostic Imaging, The University of Texas, M. D. Anderson Cancer Center, Houston, TX

Lyn kinase functions as a regulator of imatinib sensitivity in chronic myelogenous leukemia (CML) cells through an unknown mechanism. In patients who fail imatinib therapy but have no detectable BCR-ABL kinase mutation, we detected persistently activated Lyn kinase. In imatinib-resistant CML cells and patients, Lyn activation is BCR-ABL independent, it is complexed with the Gab2 and c-Cbl adapter/scaffold proteins, and it mediates persistent Gab2 and BCR-ABL tyrosine phosphorylation in the presence or absence of imatinib. Lyn silencing or inhibition is necessary to suppress Gab2 and BCR-ABL phosphorylation and to recover imatinib activity. Lyn also negatively regulates c-Cbl stability, whereas c-Cbl tyrosine phosphorylation is mediated by BCR-ABL. These results suggest that Lyn exists as a component of the BCR-ABL signaling complex and, in cells with high Lyn expression or activation, BCR-ABL kinase inhibition alone (imatinib) is not sufficient to fully disengage BCR-ABL–mediated signaling and suggests that BCR-ABL and Lyn kinase inhibition are needed to prevent or treat this form of imatinib resistance.


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 JNCI J Natl Cancer InstHome page
T. O'Hare, C. A. Eide, and M. W. Deininger
Persistent LYN Signaling in Imatinib-Resistant, BCR-ABL-Independent Chronic Myelogenous Leukemia
J Natl Cancer Inst, July 2, 2008; 100(13): 908 - 909.
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