Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction

Copland, M., Hamilton, A., Eirick, L., Baird, J., Allan, E., Jordanides, N., Barow, M., Mountford, J. and Holyoake, T. (2006) Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood, 107(11), pp. 4532-4539. (doi:10.1182/blood-2005-07-2947)

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Abstract

Dasatinib (BMS-354825), a novel dual SRC/BCR-ABL kinase inhibitor, exhibits greater potency than imatinib mesylate (IM) and inhibits the majority of kinase mutations in IM-resistant chronic myeloid leukemia (CIVIL). We have previously demonstrated that IM reversibly blocks proliferation but does not induce apoptosis of primitive CIVIL cells. Here, we have attempted to overcome this resistance with dasatinib. Primitive IM-resistant CML cells showed only single-copy BCR-ABL but expressed significantly higher BCR-ABL transcript levels and BCR-ABL protein compared with more mature CML cells (P = .031). In addition, CrKL phosphorylation was higher in the primitive CD34(+)CD38(-) than in the total CD34(+) population (P = .002). In total CD34(+) CIVIL cells, IM inhibited phosphorylation of CrKL at 16 but not 72 hours, consistent with enrichment of an IM-resistant primitive population. CD34(+)CD38(-) CML cells proved resistant to IM-induced inhibition of CrKL phosphorylation and apoptosis, whereas dasatinib led to significant inhibition of CrKL phosphorylation. Kinase domain mutations were not detectable in either IM or dasatinib-resistant primitive CML cells. These data confirm that dasatinib is more effective than IM within the CML stem cell compartment; however, the most primitive quiescent CML cells appear to be inherently resistant to both drugs.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Mountford, Dr Jo and Copland, Professor Mhairi
Authors: Copland, M., Hamilton, A., Eirick, L., Baird, J., Allan, E., Jordanides, N., Barow, M., Mountford, J., and Holyoake, T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Blood
ISSN:0006-4971

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
354131Novel drug combinations for eradication of Ph+/Bcr-Abl+ haemopoietic stem cells in chronic myeloid leukaemia (CML)Mhairi CoplandMedical Research Council (MRC)G84/6317Institute of Cancer Sciences