Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival

Hamilton, A. et al. (2012) Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood, 119(6), pp. 1501-1510. (doi: 10.1182/blood-2010-12-326843)

Abstract

Recent evidence suggests CML stem cells are insensitive to kinase inhibitors and responsible for minimal residual disease in treated patients. We investigated whether CML stem cells, in a transgenic mouse model of CML-like disease or derived from patients, are dependent on Bcr-Abl. In the transgenic model, following re-transplantation, donor-derived CML stem cells in which Bcr-Abl expression had been induced and subsequently shut off, were able to persist in vivo and re-initiate leukemia in secondary recipients upon Bcr-Abl re-expression. Bcr-Abl knockdown in human CD34+ CML cells cultured for 12 days in physiological growth factors achieved partial inhibition of Bcr-Abl and downstream targets p-CrkL and p-STAT5, inhibition of proliferation and colony forming cells, but no reduction of input cells. The addition of dasatinib further inhibited p-CrkL and p-STAT5, yet only reduced input cells by 50%. Complete growth factor withdrawal plus dasatinib further reduced input cells to 10%, however the surviving fraction was enriched for primitive leukemic cells capable of growth in long-term culture initiating cell assay and expansion upon removal of dasatinib and addition of growth factors. Together these data suggest that CML stem cell survival is Bcr-Abl kinase independent and suggest curative approaches in CML must focus on kinase-independent mechanisms of resistance.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Holyoake, Professor Tessa and Zhang, Dr Bin and Hamilton, Ms Ashley and Brunton, Dr Valerie and Helgason, Professor Vignir and Allan, Mrs Elaine
• Authors: Hamilton, A., Helgason, G. V., Schemionek, M., Zhang, B., Myssina, S., Allan, E. K., Nicolini, F. E., Muller-Tidow, C., Bhatia, R., Brunton, V. G., Koschmieder, S., and Holyoake, T. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Blood
• Publisher: American Society of Hematology
• ISSN: 0006-4971
• ISSN (Online): 1528-0020
• Published Online: 19 December 2011

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Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
43923	1	Is Bcr-Able expression relevant for the survival of cancer stem cells in chronic myeloid leukaemia	Tessa Holyoake	Medical Research Council (MRC)	G0600782	RI CANCER SCIENCES