title: A novel mouse model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression.
abstract: 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.
authors: 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.
authors: George
authors: G
authors: Giotopoulos
authors: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors: Louise
authors: L
authors: van der Weyden
authors: 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.
authors: Hikari
authors: H
authors: Osaki
authors: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK Tumour Profiling Unit, The Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, England, UK.
authors: Alistair G
authors: AG
authors: Rust
authors: 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.
authors: Paolo
authors: P
authors: Gallipoli
authors: 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.
authors: Eshwar
authors: E
authors: Meduri
authors: 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.
authors: Sarah J
authors: SJ
authors: Horton
authors: 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.
authors: Wai-In
authors: WI
authors: Chan
authors: 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.
authors: Donna
authors: D
authors: Foster
authors: Epinova DPU, GlaxoSmithKline, Medicines Research Centre, Stevenage SG1 2NY, England, UK.
authors: Rab K
authors: RK
authors: Prinjha
authors: Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
authors: John E
authors: JE
authors: Pimanda
authors: Cancer Science Institute, National University of Singapore, Singapore 119077 Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.
authors: Daniel G
authors: DG
authors: Tenen
authors: Haematological Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, England, UK.
authors: George S
authors: GS
authors: Vassiliou
authors: Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52062 Aachen, Germany.
authors: Steffen
authors: S
authors: Koschmieder
authors: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors: David J
authors: DJ
authors: Adams
authors: 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 bjph2@cam.ac.uk.
authors: Brian J P
authors: BJ
authors: Huntly
mesh_terms: D000818:Animals; D004251:DNA Transposable Elements; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D020570:Genes, myb; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods; D016254:Mutagenesis, Insertional; D009154:Mutation; D014407:Tumor Cells, Cultured; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics
chemical_list: D004251:DNA Transposable Elements; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse; D016044:Fusion Proteins, bcr-abl