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Originally published In Press as doi:10.1074/jbc.M402290200 on June 2, 2004

J. Biol. Chem., Vol. 279, Issue 33, 34227-34239, August 13, 2004
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A Bcr/Abl-independent, Lyn-dependent Form of Imatinib Mesylate (STI-571) Resistance Is Associated with Altered Expression of Bcl-2*

Yun Dai{ddagger}, Mohamed Rahmani{ddagger}, Seth J. Corey§, Paul Dent¶, and Steven Grant{ddagger}||**{ddagger}{ddagger}

From the Departments of {ddagger}Medicine, ||Biochemistry, **Pharmacology, and Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23298 and the §Department of Pediatrics, University of Texas M. D. Anderson Center, Houston, Texas 77030

The relationship between the Src kinase Lyn and Bcl-2 expression was examined in chronic myelogenous leukemia cells (K562 and LAMA84) displaying a Bcr/Abl-independent form of imatinib mesylate resistance. K562-R and LAMA-R cells that were markedly resistant to induction of mitochondrial dysfunction (e.g. loss of mitochondrial membrane potential, Bax translocation, cytochrome c, and apoptosis-inducing factor release) and apoptosis by imatinib mesylate exhibited a pronounced reduction in expression of Bcr/Abl, Bcl-xL, and STAT5 but a striking increase in levels of activated Lyn. Whereas basal expression of Bcl-2 protein was very low in parental cells, imatinib-resistant cells displayed a marked increase in Bcl-2 mRNA and/or protein levels. Treatment of LAMA-R cells with the Src kinase inhibitor PP2 significantly reduced Lyn activation as well as Bcl-2 mRNA and protein levels. Transient or stable transfection of LAMA84 or K562 cells with a constitutively active Lyn (Y508F), but not with a kinase-dead mutant (K275D), significantly increased Bcl-2 protein expression and protected cells from lethality of imatinib mesylate. Ectopic expression of Bcl-2 protected K562 and LAMA84 cells from imatinib mesylate- and PP2-mediated lethality. Conversely, interference with Bcl-2 function by co-administration of the small molecule Bcl-2 inhibitor HA14-1 or down-regulation of Bcl-2 expression by small interfering RNA or antisense strategies significantly increased mitochondrial dysfunction and apoptosis induced by imatinib mesylate and the topoisomerase inhibitor VP-16 in LAMA-R cells. In marked contrast, these interventions had little effect in parental LAMA84 cells that display low basal levels of Bcl-2. Together, these findings indicate that activation of Lyn in leukemia cells displaying a Bcr/Abl-independent form of imatinib mesylate resistance plays a functional role in Bcl-2 up-regulation and provide a theoretical basis for the development of therapeutic strategies targeting Bcl-2 in such a setting.

Received for publication, March 1, 2004 , and in revised form, June 2, 2004.

* This work was supported by National Institutes of Health Grants CA63753, CA93738, CA100866, CA88906, and CA72955, Translational Research Award 6045-03 from the Leukemia and Lymphoma Society of America, Department of Defense Award DAMD-17-03-1-0209), a V Foundation award, and by a Universal Professorship (to P. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{ddagger}{ddagger} To whom correspondence should be addressed: Division of Hematology/Oncology, MCV Station Box 230, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA 23298. Tel.: 804-828-5211; Fax: 804-828-8079; E-mail: stgrant{at}hsc.vcu.edu.


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