title: Bortezomib induces apoptosis in primitive chronic myeloid leukemia cells including LTC-IC and NOD/SCID repopulating cells.
abstract: Chronic myeloid leukemia (CML) is treated effectively with tyrosine kinase inhibitors (TKIs); however, 2 key problems remain-the insensitivity of CML stem and progenitor cells to TKIs and the emergence of TKI-resistant BCR-ABL mutations. BCR-ABL activity is associated with increased proteasome activity and proteasome inhibitors (PIs) are cytotoxic against CML cell lines. We demonstrate that bortezomib is antiproliferative and induces apoptosis in chronic phase (CP) CD34+ CML cells at clinically achievable concentrations. We also show that bortezomib targets primitive CML cells, with effects on CD34+38(-), long-term culture-initiating (LTC-IC) and nonobese diabetic/severe combined immunodeficient (NOD/SCID) repopulating cells. Bortezomib is not selective for CML cells and induces apoptosis in normal CD34+38(-) cells. The effects against CML cells are seen when bortezomib is used alone and in combination with dasatinib. Bortezomib causes proteasome but not BCR-ABL inhibition and is also effective in inhibiting proteasome activity and inducing apoptosis in cell lines expressing BCR-ABL mutations, including T315I. By targeting both TKI-insensitive stem and progenitor cells and TKI-resistant BCR-ABL mutations, we believe that bortezomib offers a potential therapeutic option in CML. Because of known toxicities, including myelosuppression, the likely initial clinical application of bortezomib in CML would be in resistant and advanced disease.
authors.affiliation: Paul O'Gorman Leukaemia Research Centre, Medical Faculty, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Heaney
authors.forename: Francesca
authors.initials: F
authors.lastname: Pellicano
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Lisa
authors.initials: L
authors.lastname: Crawford
authors.forename: Su
authors.initials: S
authors.lastname: Chu
authors.forename: Syed M A
authors.initials: SM
authors.lastname: Kazmi
authors.forename: Elaine K
authors.initials: EK
authors.lastname: Allan
authors.forename: Heather G
authors.initials: HG
authors.lastname: Jorgensen
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Irvine
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D018929:Cell Culture Techniques / Q000379:methods*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D050505:Mutant Proteins / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D018952:Antigens, CD34; D001897:Boronic Acids; D050505:Mutant Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011743:Pyrimidines; D013844:Thiazoles; D000069286:Bortezomib; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib