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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.
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Submitted February 23, 2006
Accepted November 23, 2006
Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells
Geoffrey A. Bartholomeusz, Moshe Talpaz, Vaibhav Kapuria, Ling Yuan Kong, Shimei Wang, Zeev Estrov, Waldemar Priebe, Ji Wu, and Nicholas J Donato*
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
Division of Hematology/Oncology, The University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, United States
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: ndonato{at}med.umich.edu.
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, and 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 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 hematopoetic colony formation and strongly inhibited colony formation of cells derived from T315I-expressing CML patients in blast crisis. WP1130 suppressed the growth of K562 heterotransplanted tumors as well as both wild-type BCR-ABL and T315I/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.
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