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Medline ® Abstract for Reference 168

of 'Cellular and molecular biology of chronic myeloid leukemia'

168
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A novel mouse model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression.
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Giotopoulos G, van der Weyden L, Osaki H, Rust AG, Gallipoli P, Meduri E, Horton SJ, Chan WI, Foster D, Prinjha RK, Pimanda JE, Tenen DG, Vassiliou GS, Koschmieder S, Adams DJ, Huntly BJ
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J Exp Med. 2015;212(10):1551. Epub 2015 Aug 24.
 
The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is dependent on BCR-ABL, additional mutations are required for progression to BC. However, the identity of these mutations and the pathways they affect are poorly understood, hampering our ability to identify therapeutic targets and improve outcomes. Here, we describe a novel mouse model that allows identification of mechanisms of BC progression in an unbiased and tractable manner, using transposon-based insertional mutagenesis on the background of chronic phase CML. Our BC model is the first to faithfully recapitulate the phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease.
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Department of Haematology, Cambridge Institute for Medical Research and Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0XY, England, UK Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1TN, England, UK.
PMID