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

Hamilton, Ashley, Helgason, G Vignir, Schemionek, Mirle, Zhang, Bin, Mysina, Svetlana, Allan, Elaine K, Nicolini, Franck E, Müller-Tidow, Carsten, Bhatia, Ravi, Brunton, Valerie G, Koschmieder, Steffen and Holyoake, Tessa L (2012) Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood, 119 (6). pp. 1501-10. ISSN 1528-0020

Item Type: Article

Abstract

Recent evidence suggests chronic myeloid leukemia (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, after retransplantation, donor-derived CML stem cells in which Bcr-Abl expression had been induced and subsequently shut off were able to persist in vivo and reinitiate leukemia in secondary recipients on Bcr-Abl reexpression. Bcr-Abl knockdown in human CD34(+) CML cells cultured for 12 days in physiologic 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 a long-term culture-initiating cell assay and expansion on 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.

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More Information

Depositing User: Svetlana Mysina

Identifiers

Item ID: 10012
ISSN: 1528-0020
URI: http://sure.sunderland.ac.uk/id/eprint/10012

Users with ORCIDS

Catalogue record

Date Deposited: 08 Oct 2018 09:55
Last Modified: 09 Oct 2018 10:34

Contributors

Author: Ashley Hamilton
Author: G Vignir Helgason
Author: Mirle Schemionek
Author: Bin Zhang
Author: Svetlana Mysina
Author: Elaine K Allan
Author: Franck E Nicolini
Author: Carsten Müller-Tidow
Author: Ravi Bhatia
Author: Valerie G Brunton
Author: Steffen Koschmieder
Author: Tessa L Holyoake

Subjects

Sciences > Biomedical Sciences
Sciences

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