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

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

  • Blood. 2008 Apr 1;111(7):3821-9. doi: 10.1182/blood-2007-08-109330.
Ji Wu 1 Feng Meng Henry Lu Ling Kong William Bornmann Zhenghong Peng Moshe Talpaz Nicholas J Donato
Affiliations

Affiliation

  • 1 Department of Experimental Therapeutics, The University of Texas, M. D. Anderson Cancer Center, Houston, USA.
Abstract

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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