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Prepublished online as a Blood First Edition Paper on June 7, 2002; DOI 10.1182/blood-2002-05-1361. This Article Abstract Full Text (PDF) All Versions of this Article: 2002-05-1361v1 100/8/3041    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gorre, M. E. Articles by Sawyers, C. L. Search for Related Content PubMed PubMed Citation Articles by Gorre, M. E. Articles by Sawyers, C. L. Related Collections Neoplasia Oncogenes and Tumor Suppressors Brief Reports Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 October 2002, Vol. 100, No. 8, pp. 3041-3044 BRIEF REPORT BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90 Mercedes E. Gorre, Katharine Ellwood-Yen, Gabriela Chiosis, Neal Rosen, and Charles L. Sawyers From the Department of Medicine and Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, CA; the Department of Medicine and Program in Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY.     Abstract Top Abstract Introduction Study design Results and discussion References Clinical resistance to imatinib mesylate is commonly observed in patients with advanced Philadelphia chromosome- positive (Ph+) leukemias. Acquired resistance is typically associated with reactivation of BCR-ABL due to kinase domain mutations or gene amplification, indicating that BCR-ABL remains a viable target for inhibition in these patients. Strategies for overcoming resistance can be envisioned through exploitation of other molecular features of the BCR-ABL protein, such as its dependence on the molecular chaperone heat shock protein 90 (Hsp90). To determine whether inhibition of Hsp90 could induce degradation of imatinib mesylate-resistant, mutant BCR-ABL proteins, hematopoietic cells expressing 2 mutant BCR-ABL proteins found in imatinib mesylate-resistant patients (T315I and E255K) were examined for sensitivity to geldanamycin and 17-allylaminogeldanamycin (17-AAG). Both compounds induced the degradation of wild-type and mutant BCR-ABL and inhibited cell growth, with a trend indicating more potent activity against mutant BCR-ABL proteins. These data support clinical investigations of 17-AAG in imatinib mesylate-resistant Ph+ leukemias. (Blood. 2002;100:3041-3044) © 2002 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References Chronic myeloid leukemia (CML) is a pluripotent hematopoietic stem cell disorder characterized by the Philadelphia (Ph) chromosome translocation.1,2 The resulting BCR-ABL fusion gene encodes a cytoplasmic protein with constitutive tyrosine kinase activity.3 Numerous experimental models have established that BCR-ABL is an oncogene and is sufficient to produce CML-like disease in mice.4,5 CML progresses through distinct clinical stages termed chronic phase, accelerated phase, and blast crisis. The BCR-ABL oncogene is expressed at all stages, but blast crisis is characterized by multiple additional genetic and molecular changes. Because the BCR-ABL kinase is deemed necessary for the deregulated growth of leukemic cells, it provides an ideal target for inhibition in the treatment of CML and other Ph+ leukemias. In clinical trials, imatinib mesylate (Gleevec), a 2-phenylamino pyrimidine that targets the adenosine triphosphate (ATP)-binding site of the kinase domain of ABL, induced remissions in patients with chronic phase CML as well as blast crisis.6,7 However, while responses in chronic phase were durable, remissions observed in blast crisis patients were typically short-lived with relapse occurring within 6 months despite continued therapy.7 In patients with transient responses to imatinib mesylate, acquired resistance has typically been associated with failure to maintain effective inhibition of BCR-ABL kinase activityan indication that BCR-ABL remains a viable target for inhibition in these patients.8 Mechanisms of resistance in relapsed patients include BCR-ABL gene amplification and kinase domain mutations, such as T315I and E255K, which alter the targeted region of the protein and therefore abrogate imatinib mesylate binding.8-12 Strategies for overcoming resistance associated with kinase domain mutations will likely require targeting other molecular features of the BCR-ABL protein. Heat shock protein 90 (Hsp90) is a molecular chaperone which affects the stability and function of multiple oncogenic proteins including BCR-ABL.13,14 Geldanamycin (GA) is a benzoquinone ansamycin which specifically inhibits Hsp90 by competitively binding to an ATP-binding pocket in the amino-terminus of Hsp90.15-17 Disruption of Hsp90 function by GA or its less toxic analog, 17-allylaminogeldanamycin (17-AAG), in BCR-ABL-expressing leukemia cells has been shown to induce BCR-ABL protein degradation and suppress cell proliferation.13,18,19 17-AAG is currently in phase I clinical trials. To determine whether inhibition of Hsp90 could induce degradation of imatinib mesylate-resistant, mutant BCR-ABL proteins, hematopoietic cells expressing 2 mutant BCR-ABL proteins found in imatinib mesylate-resistant patients (T315I and E255K) were derived and tested for sensitivity to GA and 17-AAG. We found that both compounds induced the degradation of wild-type and mutant BCR-ABL proteins as well as inhibited cell growth. The data also suggest a trend indicating a greater potency against mutant BCR-ABL proteins. These results provide a rationale for the use of 17-AAG in the clinical setting of imatinib mesylate-resistant Ph+ leukemia.     Study design Top Abstract Introduction Study design Results and discussion References Chemicals Stock solutions of GA (Sigma, St Louis, MO), 17-AAG (NSC 330507, National Cancer Institute, Bethesda, MD), and imatinib mesylate (Novartis, Basel, Switzerland) were prepared as 10 mM dimethylsulfoxide solutions and stored at 20°C. Plasmids and cell lines Full-length P210 T315I and P210 E255K BCR-ABL in pBluescript (Stratagene, La Jolla, CA) were generated using site-directed mutagenesis and confirmed by sequencing as described previously.8 Wild-type and mutant P210 BCR-ABL were subsequently subcloned into the EcoRI site of pMSCVpuro (Clontech, Palo Alto, CA) for retrovirus generation. Ecotropic retroviruses were generated by cotransfection of pMSCVpuro DNA and Ecopac retroviral packaging vector (kindly provided by R. Van Etten) into 293T cells using the CaCl2 method.20 The murine hematopoietic cell line Ba/F3 was maintained in RPMI1640 supplemented with 10% fetal bovine serum, L-glutamine, and 1 ng/mL recombinant murine IL-3 (R&D, Minneapolis, MN). Ba/F3 populations with stable BCR-ABL expression were derived by retroviral infection of Ba/F3 cells in the presence of IL-3, and subsequent selection by puromycin. IL-3-independent BCR-ABL-expressing cells were derived by culturing in IL-3-free media at low densities in 96-well tissue culture plates. Multiple IL-3-independent populations were assayed for comparable BCR-ABL protein expression by Western blot. In vitro drug exposure assays Cells were cultured in 24-well plates at 2 × 105 cells/mL in growth media (plus IL-3 for parental cells) with GA, 17-AAG, or imatinib mesylate for 24 or 48 hours. Subsequent analyses of protein by Western blot or cell viability by trypan blue dye exclusion were done as previously described.8,21     Results and discussion Top Abstract Introduction Study design Results and discussion References Previous studies have shown that the Hsp90 inhibitors GA and its derivative, 17-AAG, disrupt Hsp90 function and induce BCR-ABL protein degradation.13,18,19 To determine whether GA can similarly cause the degradation of BCR-ABL proteins carrying imatinib mesylate-resistant point mutations, populations of interleukin-3 (IL-3)-dependent Ba/F3 murine hematopoietic cells were engineered to express either wild-type, T315I, or E255K P210 BCR-ABL and exposed to varying concentrations of inhibitor. Consistent with previous reports, both mutant BCR-ABL alleles rendered the cells independent of IL-3, and cells expressing either mutant contained high levels of phosphotyrosine on BCR-ABL and other substrate proteins (data not shown).8,11 Western blot analyses using ABL-specific antibodies demonstrated that GA caused BCR-ABL protein levels to decrease significantly in cells expressing wild-type BCR-ABL after treatment for 24 hours at a dose of 1.0 µM, as expected.13,18,19 BCR-ABL protein was also degraded in cells expressing either T315I or E255K BCR-ABL, but this degradation occurred at a lower GA concentration (0.5 µM) (Figure 1A). This apparently enhanced degradation of the 2 mutant BCR-ABL proteins was specific because degradation of another Hsp90 client protein, RAF-1, was comparable in all cells tested. These data suggest that GA may have greater potency against mutant BCR-ABL proteins compared with wild type. View larger version (67K): [in this window] [in a new window]   Figure 1. Geldanamycin and 17-AAG induce degradation of wild-type and imatinib mesylate-resistant, mutant BCR-ABL proteins and inhibit BCR-ABL signaling. (A) Ba/F3 cells expressing wild-type, T315I, or E255K BCR-ABL were incubated in the presence of increasing concentrations of geldanamycin (GA) for 24 hours. Immunoblotting of cell lysates was performed with anti-ABL (Ab3, Oncogene, San Diego, CA) (upper panels), anti-RAF-1 (Santa Cruz Biotechnology, Santa Cruz, CA) (middle panels), and antiactin (ac-15, Sigma) as a control for protein loading (lower panels). (B) Ba/F3 cells expressing wild-type, T315I, or E255K BCR-ABL were incubated in the presence of increasing concentrations of 17-AAG for 24 hours. Immunoblotting of these lysates was performed with anti-ABL (upper panels) and antiactin as a control for protein loading (lower panels). (C) Immunoblotting of the same lysates from (B) was performed with anti-CRKL (Santa Cruz). CRKL, when tyrosine-phosphorylated, migrates more slowly on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) resulting in an upper band representing phosphorylated CRKL (P-CRKL) and a lower band representing nonphosphorylated CRKL. (D) Densitometric analysis of CRKL immunoblot shown in (C) using ImageQuant software (Molecular Dynamics, Sunnyvale, CA). Quantified CRKL phosphorylation is expressed as percentage of phosphorylated CRKL over total CRKL protein (% P-CRKL). (E) Densitometric analysis of CRKL immunoblot using lysates from the same Ba/F3 cell lines incubated in the presence of increasing concentrations of imatinib mesylate for 24 hours. We next tested 17-AAGa GA derivative currently in phase I clinical trialsfor its ability to induce BCR-ABL protein degradation in the same Ba/F3 cell lines. Western blot analyses of lysates from cells cultured in 17-AAG showed a similar trend to that seen with GA. Wild-type BCR-ABL protein levels fell gradually after 24 hours of exposure to 0.5 to 1.0 µM 17-AAG. Although BCR-ABL protein levels in both the T315I and E255K BCR-ABL-expressing cells began to decline at a similar concentration of 17-AAG as wild-type BCR-ABL (0.5 µM), the magnitude of decrease was more dramatic in cells expressing the BCR-ABL mutants. Virtually no BCR-ABL protein was detectable at 1.0 µM of 17-AAG for both mutants (Figure 1B). This trend was confirmed when we assessed the effect of 17-AAG on downstream BCR-ABL signaling by measuring the phosphorylation status of CRKL, a direct BCR-ABL substrate with functional relevance in CML.22-25 Western blot analysis using CRKL-specific antisera on lysates from cells incubated in the presence of increasing concentrations of imatinib mesylate confirmed that the BCR-ABL mutants conferred resistance to imatinib mesylate (Figure 1E). CRKL Western blot analysis on lysates from17-AAG-treated cells revealed that lower doses of 17-AAG were needed to inhibit BCR-ABL activity in cells expressing the BCR-ABL mutants when compared with wild-type BCR-ABL (Figure 1C-D). Significant changes in CRKL phosphorylation were not observed in wild-type BCR-ABL-expressing cells until a 17-AAG concentration of 5.0 µM was reached, whereas CRKL phosphorylation in T315I and E255K BCR-ABL-expressing cells was significantly inhibited at 0.5 µM of drug (Figure 1C-D). Although we cannot rule out the possibility that 17-AAG may affect another kinase which plays a role in CRKL phosphorylation in these cells, the fact that 17-AAG also reduced the level of BCR-ABL protein, together with previously published data showing that constitutively elevated CRKL phosphorylation is relatively specific for CML,22 strongly suggests that BCR-ABL is the target. Previous studies have also shown that GA and 17-AAG inhibit growth and induce apoptosis of BCR-ABL-positive leukemic cell lines.18,19 To determine whether GA could inhibit growth in cells expressing imatinib mesylate-resistant BCR-ABL mutants, Ba/F3 cells transformed by wild-type, T315I, and E255K BCR-ABL were cultured in a range of GA concentrations. Trypan blue dye exclusion assessments of viability and corresponding IC50 calculations (the concentration of inhibitor required to reduce the number of viable cells by 50%) indicated that the growth of all 3 BCR-ABL-positive cell lines was inhibited by GA at lower doses when compared with BCR-ABL-negative parental cells (Table 1). The enhanced sensitivity of the imatinib mesylate-resistant BCR-ABL mutants compared with wild-type BCR-ABL observed in the biochemical analyses was also recapitulated in the growth inhibition assays. Similar results were observed with 17-AAG-treated cells. All BCR-ABL-expressing cells were more sensitive to 17-AAG than Ba/F3 parental cells, with the imatinib mesylate-resistant BCR-ABL-expressing cells again displaying a heightened sensitivity to inhibition compared with wild-type BCR-ABL-expressing cells (Table 1).                                View this table: [in this window] [in a new window]   Table 1. Sensitivity of imatinib mesylate-resistant BCR-ABL-transformed cells to geldanamycin and 17-AAG In summary, targeted inhibition of Hsp90 with either GA or 17-AAG induced the degradation of wild-type BCR-ABL and 2 imatinib mesylate-resistant BCR-ABL mutants, T315I and E255K. Both compounds also inhibited the growth of hematopoietic cells transformed by wild-type and mutant BCR-ABL. The results also suggest that the imatinib mesylate-resistant mutants are more sensitive to Hsp90 inhibition than wild-type BCR-ABL. One potential explanation could be that these 2 mutant proteins are less stable than wild-type BCR-ABL, and therefore more dependent on molecular chaperones. A better understanding of the variables that determine the relative dependence of client proteins on Hsp90 function is required to fully evaluate this question. Nevertheless, these data provide support for clinical investigations of 17-AAG in imatinib mesylate-resistant Ph+ leukemia.     Acknowledgments We wish to thank Randy Chen for expert technical assistance.     Footnotes Submitted May 9, 2002; accepted May 30, 2002. Prepublished online as Blood First Edition Paper, June 7, 2002; DOI 10.1182/blood-2002-05-1361. Supported by grants from the Leukemia and Lymphoma Society, the National Cancer Institute (C.L.S.) and USPHS National Research Service Award GM07185 (M.E.G.). C.L.S. is a Doris Duke Distinguished Clinical Scientist. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Charles L. Sawyers, David Geffen School of Medicine at UCLA, Division of Hematology and Oncology, 11-934 Factor Bldg 10833 Le Conte Ave, Los Angeles, CA 90095-1678; e-mail: csawyers{at}mednet.ucla.edu.     References Top Abstract Introduction Study design Results and discussion References 1. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340:1330-1340[Free Full Text]. 2. Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 1999;341:164-172[Free Full Text]. 3. Konopka JB, Watanabe SM, Singer JW, Collins SJ, Witte ON. Cell lines and clinical isolates derived from Ph1-positive chronic myelogenous leukemia patients express c-abl proteins with a common structural alteration. Proc Natl Acad Sci U S A. 1985;82:1810-1814[Abstract/Free Full Text]. 4. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824-830[Abstract/Free Full Text]. 5. Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990;344:251-253[CrossRef][Medline] [Order article via Infotrieve]. 6. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037[Abstract/Free Full Text]. 7. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038-1042[Abstract/Free Full Text]. 8. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876-880[Abstract/Free Full Text]. 9. Branford S, Rudzki Z, Walsh S, et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood. 2002;99:3472-3475[Abstract/Free Full Text]. 10. Hofmann WK, Jones LC, Lemp NA, et al. Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation. Blood. 2002;99:1860-1862[Abstract/Free Full Text]. 11. von Bubnoff N, Schneller F, Peschel C, Duyster J. BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet. 2002;359:487-491[CrossRef][Medline] [Order article via Infotrieve]. 12. Shah NP, Nicoll J, Gorre ME, Paquette R, Ford J, Sawyers CL. Resistance to Gleevec: sequence analysis reveals a spectrum of BCR/ABL kinase domain mutations in both acquired and de novo-resistant cases of CML in myeloid blast crisis. American Society of Hematology 43rd Annual Meeting. Orlando: FL; 2001. 13. An WG, Schulte TW, Neckers LM. The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210bcr-abl and v-src proteins before their degradation by the proteasome. Cell Growth Differ. 2000;11:355-360[Abstract/Free Full Text]. 14. Shiotsu Y, Neckers LM, Wortman I, et al. Novel oxime derivatives of radicicol induce erythroid differentiation associated with preferential G(1) phase accumulation against chronic myelogenous leukemia cells through destabilization of Bcr-Abl with Hsp90 complex. Blood. 2000;96:2284-2291[Abstract/Free Full Text]. 15. Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell. 1997;90:65-75[CrossRef][Medline] [Order article via Infotrieve]. 16. Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP. Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell. 1997;89:239-250[CrossRef][Medline] [Order article via Infotrieve]. 17. Grenert JP, Sullivan WP, Fadden P, et al. The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation. J Biol Chem. 1997;272:23843-23850[Abstract/Free Full Text]. 18. Blagosklonny MV, Fojo T, Bhalla KN, et al. The Hsp90 inhibitor geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic chemotherapy. Leukemia. 2001;15:1537-1543[CrossRef][Medline] [Order article via Infotrieve]. 19. Nimmanapalli R, O'Bryan E, Bhalla K. Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. Cancer Res. 2001;61:1799-1804[Abstract/Free Full Text]. 20. Muller AJ, Young JC, Pendergast AM, et al. BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias. Mol Cell Biol. 1991;11:1785-1792[Abstract/Free Full Text]. 21. Goga A, McLaughlin J, Afar DE, Saffran DC, Witte ON. Alternative signals to RAS for hematopoietic transformation by the BCR-ABL oncogene. Cell. 1995;82:981-988[CrossRef][Medline] [Order article via Infotrieve]. 22. Nichols GL, Raines MA, Vera JC, Lacomis L, Tempst P, Golde DW. Identification of CRKL as the constitutively phosphorylated 39-kD tyrosine phosphoprotein in chronic myelogenous leukemia cells. Blood. 1994;84:2912-2918[Abstract/Free Full Text]. 23. Oda T, Heaney C, Hagopian JR, Okuda K, Griffin JD, Druker BJ. Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. J Biol Chem. 1994;269:22925-22928[Abstract/Free Full Text]. 24. Senechal K, Halpern J, Sawyers CL. The CRKL adaptor protein transforms fibroblasts and functions in transformation by the BCR-ABL oncogene. J Biol Chem. 1996;271:23255-23261[Abstract/Free Full Text]. 25. ten Hoeve J, Arlinghaus RB, Guo JQ, Heisterkamp N, Groffen J. Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia. Blood. 1994;84:1731-1736[Abstract/Free Full Text]. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T.-S. Lee, W. Ma, X. Zhang, F. Giles, J. Cortes, H. Kantarjian, and M. Albitar BCR-ABL alternative splicing as a common mechanism for imatinib resistance: evidence from molecular dynamics simulations Mol. Cancer Ther., December 1, 2008; 7(12): 3834 - 3841. [Abstract] [Full Text] [PDF] T. P. Hughes, S. Branford, D. L. White, J. Reynolds, R. Koelmeyer, J. F. Seymour, K. Taylor, C. Arthur, A. Schwarer, J. Morton, et al. 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Chem., August 4, 2006; 281(31): 21710 - 21719. [Abstract] [Full Text] [PDF] W. Fiskus, M. Pranpat, P. Bali, M. Balasis, S. Kumaraswamy, S. Boyapalle, K. Rocha, J. Wu, F. Giles, P. W. Manley, et al. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells Blood, July 15, 2006; 108(2): 645 - 652. [Abstract] [Full Text] [PDF] T. K. Nguyen, M. Rahmani, N. Gao, L. Kramer, A. S. Corbin, B. J. Druker, P. Dent, and S. Grant Synergistic interactions between DMAG and mitogen-activated protein kinase kinase 1/2 inhibitors in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate. Clin. Cancer Res., April 1, 2006; 12(7 Pt 1): 2239 - 2247. [Abstract] [Full Text] [PDF] K. Bhalla Overview and Cytoplasmic Targets of HDAC Inhibitors Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 309 - 312. [Full Text] [PDF] J. Chandra, J. Tracy, D. Loegering, K. Flatten, S. Verstovsek, M. Beran, M. Gorre, Z. Estrov, N. Donato, M. Talpaz, et al. Adaphostin-induced oxidative stress overcomes BCR/ABL mutation-dependent and -independent imatinib resistance Blood, March 15, 2006; 107(6): 2501 - 2506. [Abstract] [Full Text] [PDF] F. Guo, K. Rocha, P. Bali, M. Pranpat, W. Fiskus, S. Boyapalle, S. Kumaraswamy, M. Balasis, B. Greedy, E. S. M. Armitage, et al. Abrogation of Heat Shock Protein 70 Induction as a Strategy to Increase Antileukemia Activity of Heat Shock Protein 90 Inhibitor 17-Allylamino-Demethoxy Geldanamycin Cancer Res., November 15, 2005; 65(22): 10536 - 10544. [Abstract] [Full Text] [PDF] J. Cortes and H. Kantarjian New Targeted Approaches in Chronic Myeloid Leukemia J. Clin. Oncol., September 10, 2005; 23(26): 6316 - 6324. [Abstract] [Full Text] [PDF] T. A. Carter, L. M. Wodicka, N. P. Shah, A. M. Velasco, M. A. Fabian, D. K. Treiber, Z. V. Milanov, C. E. Atteridge, W. H. Biggs III, P. T. Edeen, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases PNAS, August 2, 2005; 102(31): 11011 - 11016. [Abstract] [Full Text] [PDF] T. Shimamura, A. M. Lowell, J. A. Engelman, and G. I. Shapiro Epidermal Growth Factor Receptors Harboring Kinase Domain Mutations Associate with the Heat Shock Protein 90 Chaperone and Are Destabilized following Exposure to Geldanamycins Cancer Res., July 15, 2005; 65(14): 6401 - 6408. [Abstract] [Full Text] [PDF] P.-H. Tseng, H.-P. Lin, J. Zhu, K.-F. Chen, E. M. Hade, D. C. Young, J. C. Byrd, M. Grever, K. Johnson, B. J. Druker, et al. Synergistic interactions between imatinib mesylate and the novel phosphoinositide-dependent kinase-1 inhibitor OSU-03012 in overcoming imatinib mesylate resistance Blood, May 15, 2005; 105(10): 4021 - 4027. [Abstract] [Full Text] [PDF] R. Chen and W. Plunkett Sequential Blockade of Oncogenic Kinases Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 344 - 348. [Full Text] [PDF] M. Rahmani, E. Reese, Y. Dai, C. Bauer, L. B. Kramer, M. Huang, R. Jove, P. Dent, and S. Grant Cotreatment with Suberanoylanilide Hydroxamic Acid and 17-Allylamino 17-demethoxygeldanamycin Synergistically Induces Apoptosis in Bcr-Abl+ Cells Sensitive and Resistant to STI571 (Imatinib Mesylate) in Association with Down-Regulation of Bcr-Abl, Abrogation of Signal Transducer and Activator of Transcription 5 Activity, and Bax Conformational Change Mol. Pharmacol., April 1, 2005; 67(4): 1166 - 1176. [Abstract] [Full Text] [PDF] M. Deininger, E. Buchdunger, and B. J. Druker The development of imatinib as a therapeutic agent for chronic myeloid leukemia Blood, April 1, 2005; 105(7): 2640 - 2653. [Abstract] [Full Text] [PDF] R. Seggewiss, K. Lore, E. Greiner, M. K. Magnusson, D. A. Price, D. C. Douek, C. E. Dunbar, and A. Wiestner Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner Blood, March 15, 2005; 105(6): 2473 - 2479. [Abstract] [Full Text] [PDF] R. D. Unwin, D. W. Sternberg, Y. Lu, A. Pierce, D. G. Gilliland, and A. D. Whetton Global Effects of BCR/ABL and TEL/PDGFR{beta} Expression on the Proteome and Phosphoproteome: IDENTIFICATION OF THE RHO PATHWAY AS A TARGET OF BCR/ABL J. Biol. Chem., February 25, 2005; 280(8): 6316 - 6326. [Abstract] [Full Text] [PDF] P. George, P. Bali, S. Annavarapu, A. Scuto, W. Fiskus, F. Guo, C. Sigua, G. Sondarva, L. Moscinski, P. Atadja, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3 Blood, February 15, 2005; 105(4): 1768 - 1776. [Abstract] [Full Text] [PDF] R. Bagatell and L. Whitesell Altered Hsp90 function in cancer: A unique therapeutic opportunity Mol. Cancer Ther., August 1, 2004; 3(8): 1021 - 1030. [Abstract] [Full Text] [PDF] P. Bali, P. George, P. Cohen, J. Tao, F. Guo, C. Sigua, A. Vishvanath, A. Scuto, S. Annavarapu, W. Fiskus, et al. Superior Activity of the Combination of Histone Deacetylase Inhibitor LAQ824 and the FLT-3 Kinase Inhibitor PKC412 against Human Acute Myelogenous Leukemia Cells with Mutant FLT-3 Clin. Cancer Res., August 1, 2004; 10(15): 4991 - 4997. [Abstract] [Full Text] [PDF] P. George, P. Bali, P. Cohen, J. Tao, F. Guo, C. Sigua, A. Vishvanath, W. Fiskus, A. Scuto, S. Annavarapu, et al. Cotreatment with 17-Allylamino-Demethoxygeldanamycin and FLT-3 Kinase Inhibitor PKC412 Is Highly Effective against Human Acute Myelogenous Leukemia Cells with Mutant FLT-3 Cancer Res., May 15, 2004; 64(10): 3645 - 3652. [Abstract] [Full Text] [PDF] M. G. Mohi, C. Boulton, T.-L. Gu, D. W. Sternberg, D. Neuberg, J. D. Griffin, D. G. Gilliland, and B. G. Neel Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs PNAS, March 2, 2004; 101(9): 3130 - 3135. [Abstract] [Full Text] [PDF] A. P. Jansen, C. E. Camalier, C. Stark, and N. H. Colburn Characterization of programmed cell death 4 in multiple human cancers reveals a novel enhancer of drug sensitivity Mol. Cancer Ther., February 1, 2004; 3(2): 103 - 110. [Abstract] [Full Text] [PDF] G. Fumo, C. Akin, D. D. Metcalfe, and L. Neckers 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated, constitutively activated KIT protein in human mast cells Blood, February 1, 2004; 103(3): 1078 - 1084. [Abstract] [Full Text] [PDF] P. La Rosee, K. Johnson, A. S. Corbin, E. P. Stoffregen, E. M. Moseson, S. Willis, M. M. Mauro, J. V. Melo, M. W. Deininger, and B. J. Druker In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant Bcr-Abl-positive cell lines Blood, January 1, 2004; 103(1): 208 - 215. [Abstract] [Full Text] [PDF] M. Gardembas, P. Rousselot, M. Tulliez, M. Vigier, A. Buzyn, F. Rigal-Huguet, L. Legros, M. Michallet, C. Berthou, N. Cheron, et al. Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase Blood, December 15, 2003; 102(13): 4298 - 4305. [Abstract] [Full Text] [PDF] J. M. Goldman and J. V. Melo Chronic Myeloid Leukemia -- Advances in Biology and New Approaches to Treatment N. Engl. J. Med., October 9, 2003; 349(15): 1451 - 1464. [Full Text] [PDF] N. von Bubnoff, D. R. Veach, W. T. Miller, W. Li, J. Sanger, C. Peschel, W. G. Bornmann, B. Clarkson, and J. Duyster Inhibition of Wild-Type and Mutant Bcr-Abl by Pyrido-Pyrimidine-Type Small Molecule Kinase Inhibitors Cancer Res., October 1, 2003; 63(19): 6395 - 6404. [Abstract] [Full Text] [PDF] C. Ly, A. F. Arechiga, J. V. Melo, C. M. Walsh, and S. T. Ong Bcr-Abl Kinase Modulates the Translation Regulators Ribosomal Protein S6 and 4E-BP1 in Chronic Myelogenous Leukemia Cells via the Mammalian Target of Rapamycin Cancer Res., September 15, 2003; 63(18): 5716 - 5722. [Abstract] [Full Text] [PDF] M. W. N. Deininger and B. J. Druker Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib Pharmacol. Rev., September 1, 2003; 55(3): 401 - 423. [Abstract] [Full Text] [PDF] R. Nimmanapalli, L. Fuino, P. Bali, M. Gasparetto, M. Glozak, J. Tao, L. Moscinski, C. Smith, J. Wu, R. Jove, et al. Histone Deacetylase Inhibitor LAQ824 Both Lowers Expression and Promotes Proteasomal Degradation of Bcr-Abl and Induces Apoptosis of Imatinib Mesylate-sensitive or -refractory Chronic Myelogenous Leukemia-Blast Crisis Cells Cancer Res., August 15, 2003; 63(16): 5126 - 5135. [Abstract] [Full Text] [PDF] R. Nimmanapalli, E. O'Bryan, D. Kuhn, H. Yamaguchi, H.-G. Wang, and K. N. Bhalla Regulation of 17-AAG--induced apoptosis: role of Bcl-2, Bcl-xL, and Bax downstream of 17-AAG--mediated down-regulation of Akt, Raf-1, and Src kinases Blood, July 1, 2003; 102(1): 269 - 275. [Abstract] [Full Text] [PDF] J. A. Zonder, P. Pemberton, H. Brandt, A. N. Mohamed, and C. A. Schiffer The Effect of Dose Increase of Imatinib Mesylate in Patients with Chronic or Accelerated Phase Chronic Myelogenous Leukemia with Inadequate Hematologic or Cytogenetic Response to Initial Treatment Clin. Cancer Res., June 1, 2003; 9(6): 2092 - 2097. [Abstract] [Full Text] [PDF] A. S. Corbin, P. L. Rosee, E. P. Stoffregen, B. J. Druker, and M. W. Deininger Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib Blood, June 1, 2003; 101(11): 4611 - 4614. [Abstract] [Full Text] [PDF] E. A. Sausville Is Another Bcr-Abl Inhibitor Needed for Chronic Myelogenous Leukemia? Clin. Cancer Res., April 1, 2003; 9(4): 1233 - 1234. [Full Text] [PDF] G. Marcucci, D. Perrotti, and M. A. Caligiuri Understanding the Molecular Basis of Imatinib Mesylate Therapy in Chronic Myelogenous Leukemia and the Related Mechanisms of Resistance: Commentary re: A. N. Mohamed et al., The Effect of Imatinib Mesylate on Patients with Philadelphia Chromosome-positive Chronic Myeloid Leukemia with Secondary Chromosomal Aberrations. Clin. Cancer Res., 9: 1333-1337, 2003. Clin. Cancer Res., April 1, 2003; 9(4): 1248 - 1252. [Full Text] [PDF] J. V. Melo, T. P. Hughes, and J. F. Apperley Chronic Myeloid Leukemia Hematology, January 1, 2003; 2003(1): 132 - 152. [Abstract] [Full Text] [PDF] P. La Rosee, A. S. Corbin, E. P. Stoffregen, M. W. Deininger, and B. J. Druker Activity of the Bcr-Abl Kinase Inhibitor PD180970 against Clinically Relevant Bcr-Abl Isoforms That Cause Resistance to Imatinib Mesylate (Gleevec, STI571) Cancer Res., December 15, 2002; 62(24): 7149 - 7153. 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