Chronic myeloid leukemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal

Toofan, P., Busch, C., Morrison, H., O'Brien, S., Jørgensen, H. , Copland, M. and Wheadon, H. (2018) Chronic myeloid leukemia cells require the bone morphogenic protein pathway for cell cycle progression and self-renewal. Cell Death and Disease, 9, 927. (doi: 10.1038/s41419-018-0905-2) (PMID:30206237) (PMCID:PMC6134087)

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Leukaemic stem cell (LSC) persistence remains a major obstacle to curing chronic myeloid leukaemia (CML). The bone morphogenic protein (BMP) pathway is deregulated in CML, with altered expression and response to the BMP ligands shown to impact on LSC expansion and behaviour. In this study, we determined whether alterations in the BMP pathway gene signature had any predictive value for therapeutic response by profiling 60 CML samples at diagnosis from the UK SPIRIT2 trial and correlating the data to treatment response using the 18-month follow-up data. There was significant deregulation of several genes involved in the BMP pathway with ACV1C, INHBA, SMAD7, SNAIL1 and SMURF2 showing differential expression in relation to response. Therapeutic targeting of CML cells using BMP receptor inhibitors, in combination with tyrosine kinase inhibitor (TKI), indicate a synergistic mode of action. Furthermore, dual treatment resulted in altered cell cycle gene transcription and irreversible cell cycle arrest, along with increased apoptosis compared to single agents. Targeting CML CD34+ cells with BMP receptor inhibitors resulted in fewer cell divisions, reduced numbers of CD34+ cells and colony formation when compared to normal donor CD34+ cells, both in the presence and absence of BMP4. In an induced pluripotent stem cell (iPSC) model generated from CD34+ hematopoietic cells, we demonstrate altered cell cycle profiles and dynamics of ALK expression in CML-iPSCs in the presence and absence of BMP4 stimulation, when compared to normal iPSC. Moreover, dual targeting with TKI and BMP inhibitor prevented the self-renewal of CML-iPSC and increased meso-endodermal differentiation. These findings indicate that transformed stem cells may be more reliant on BMP signalling than normal stem cells. These changes offer a therapeutic window in CML, with intervention using BMP inhibitors in combination with TKI having the potential to target LSC self-renewal and improve long-term outcome for patients.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Toofan, Miss Parto and Jorgensen, Dr Heather and Copland, Professor Mhairi and Wheadon, Professor Helen and Morrison, Miss Heather and Busch, Caroline
Authors: Toofan, P., Busch, C., Morrison, H., O'Brien, S., Jørgensen, H., Copland, M., and Wheadon, H.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Death and Disease
Publisher:Nature Publishing Group
ISSN (Online):2041-4889
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Cell Death and Disease 9:927
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES