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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3470-3478. Prepublished online as a Blood First Edition Paper on January 3, 2007; DOI 10.1182/blood-2006-02-005579. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-02-005579v1 109/8/3470    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 Bartholomeusz, G. A. Articles by Donato, N. J. Search for Related Content PubMed PubMed Citation Articles by Bartholomeusz, G. A. Articles by Donato, N. J. Related Collections Apoptosis Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells Geoffrey A. Bartholomeusz1, Moshe Talpaz3, Vaibhav Kapuria1, Ling Yuan Kong1, Shimei Wang1, Zeev Estrov2, Waldemar Priebe1, Ji Wu1, and Nicholas J. Donato3 1 Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston; 2 Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston; 3 Division of Hematology/Oncology, The University of Michigan Comprehensive Cancer Center, Ann Arbor Imatinib mesylate (Gleevec) is effective therapy against Philadelphia chromosome–positive leukemia, but resistance develops in all phases of the disease. Bcr/Abl point mutations and other alterations reduce the kinase inhibitory activity of imatinib mesylate; thus, agents that target Bcr/Abl through unique mechanisms may be needed. Here we describe the activity of WP1130, a small molecule that specifically and rapidly down-regulates both wild-type and mutant Bcr/Abl protein without affecting bcr/abl gene expression in chronic myelogenous leukemia (CML) cells. Loss of Bcr/Abl protein correlated with the onset of apoptosis and reduced phosphorylation of Bcr/Abl substrates. WP1130 did not affect Hsp90/Hsp70 ratios within the cells and did not require the participation of the proteasomal pathway for loss of Bcr/Abl protein. WP1130 was more effective in reducing leukemic versus normal hematopoietic colony formation and strongly inhibited colony formation of cells derived from patients with T315I mutant Bcr/Abl–expressing CML in blast crisis. WP1130 suppressed the growth of K562 heterotransplanted tumors as well as both wild-type Bcr/Abl and T315I mutant Bcr/Abl–expressing BaF/3 cells transplanted into nude mice. Collectively, our results demonstrate that WP1130 reduces wild-type and T315I mutant Bcr/Abl protein levels in CML cells through a unique mechanism and may be useful in treating CML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Ramirez and J. F. DiPersio Therapy Options in Imatinib Failures Oncologist, April 1, 2008; 13(4): 424 - 434. [Abstract] [Full Text] [PDF] J. Wu, F. Meng, H. Lu, L. Kong, W. Bornmann, Z. Peng, M. Talpaz, and N. J. Donato Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells Blood, April 1, 2008; 111(7): 3821 - 3829. [Abstract] [Full Text] [PDF] S. Verstovsek, T. Manshouri, A. Quintas-Cardama, D. Harris, J. Cortes, F. J. Giles, H. Kantarjian, W. Priebe, and Z. Estrov WP1066, a Novel JAK2 Inhibitor, Suppresses Proliferation and Induces Apoptosis in Erythroid Human Cells Carrying the JAK2 V617F Mutation Clin. Cancer Res., February 1, 2008; 14(3): 788 - 796. [Abstract] [Full Text] [PDF]

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