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J. Biol. Chem., Vol. 279, Issue 34, 35604-35615, August 20, 2004

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Genomic Mechanisms of p210^BCR-ABL Signaling

INDUCTION OF HEAT SHOCK PROTEIN 70 THROUGH THE GATA RESPONSE ELEMENT CONFERS RESISTANCE TO PACLITAXEL-INDUCED APOPTOSIS^*

Sutapa Ray, Ying Lu, Scott H. Kaufmann, W. Clay Gustafson¶, Judith E. Karp||, Istvan Boldogh**, Alan P. Fields, and Allan R. Brasier

From the Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555-1060, the Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, the ^¶Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1048, the ^||Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, the ^**Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1019, and the Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224

Chronic myelogenous leukemia (CML) results from a t(9,22) translocation, producing the p210^BCR-ABL oncoprotein, a tyrosine kinase that causes transformation and chemotherapy resistance. To further understand mechanisms mediating chemotherapy resistance, we identified 556 differentially regulated genes in HL-60 cells stably expressing p210^BCR-ABL versus those expressing an empty vector using cDNA macro- and oligonucleotide microarrays. These BCR-ABL-regulated gene products play diverse roles in cellular function including apoptosis, cell cycle regulation, intracellular signaling, transcription, and cellular adhesion. In particular, we identified up-regulation of the inducible form of heat shock protein 70 (Hsp70), and further explored the mechanism for its up-regulation. In HL-60/BCR-ABL and K562 cells (expressing p210^BCR-ABL), abundant cytoplasmic Hsp70 expression was detected by immunoblot analysis. Moreover, cells isolated from bone marrow aspirates of patients in different stages of CML (chronic, aggressive, and blast crisis) express Hsp70. Expression of p210^BCR-ABL in BCR-ABL negative cells induced transcription of the proximal Hsp70 promoter. Mutational analysis mapped the major p210^BCR-ABL responsive element to a high affinity 5'(A/T)GATA(A/G)-3' "GATA" response element (GATA-RE) that binds GATA-1 in CML cells. The GATA-RE was sufficient to confer p210^BCR-ABL- and p185^BCR-ABL-mediated trans-activation to an inert promoter. Short interfering RNA mediated "knockdown" of Hsp70 expression in K562 cells induced marked sensitivity to paclitaxel-induced apoptosis. Together these findings indicate that BCR-ABL confers chemotherapeutic resistance through intracellular signaling to the GATA-RE element found in the promoter region of the anti-apoptotic Hsp70 protein. We suggest that down-regulation of the GATA-Hsp70 pathway may be useful in the treatment of chemotherapy-resistant CML.

Received for publication, February 19, 2004 , and in revised form, April 28, 2004.

^* This work was supported in part by National Institutes of Health Grants CA56869 (to A. P. F.), AI40218 (to A. R. B.), and NIEHS ES06676 (to J. Halpert, University of Texas Medical Branch). 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.

To whom correspondence should be addressed: Division of Endocrinology, MRB 8.138, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1060. Tel.: 409-772-2824; Fax: 409-772-8709; E-mail: arbrasie{at}utmb.edu.

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