The chronic myeloid leukemia stem cell: stemming the tide of persistence

Holyoake, T. L. and Vetrie, D. (2017) The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood, 129(12), pp. 1595-1606. (doi: 10.1182/blood-2016-09-696013) (PMID:28159740)

Abstract

Chronic myeloid leukaemia (CML) is caused by the acquisition of the tyrosine kinase BCR-ABL1 in a haemopoietic stem cell (HSC), transforming it into a leukaemic stem cell (LSC) that self-renews, proliferates and differentiates to give rise to a myeloproliferative disease. While tyrosine kinase inhibitors (TKI) that target the kinase activity of BCR-ABL1 have transformed CML from a once fatal disease to a manageable one for the vast majority of patients, only ~10% of those who present in chronic phase (CP) can discontinue TKI treatment and maintain a therapy-free remission. Strong evidence now shows that CML LSC are resistant to the effects of TKIs and they persist in all patients on long-term therapy, where they may promote acquired TKI resistance, drive relapse or disease progression and inevitably represent a bottleneck to cure. Since their discovery in patients almost two decades ago, CML LSC have become a well-recognised exemplar of the cancer stem cell and have been characterised extensively with the aim of developing new curative therapeutic approaches based on LSC eradication. This review summarises our current understanding of many of the pathways and mechanisms that promote the survival of the CP CML LSC and how they can be a source of new gene coding mutations that impact in the clinic. We also review recent pre-clinical approaches that show promise to eradicate the LSC, and future challenges on the path to cure.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Holyoake, Professor Tessa and Vetrie, Professor David
• Authors: Holyoake, T. L., and Vetrie, D.
• 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: 03 February 2017
• Copyright Holders: Copyright © 2017 American Society of Hematology
• First Published: First published in Blood 219(12):1595-1606
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher