Tyrosine kinase inhibitor independent gene expression signature in CML offers new targets for LSPC eradication therapy

Gómez-Castañeda, E., Hopcroft, L. E.M. , Rogers, S. , Munje, C., Bittencourt-Silvestre, J., Copland, M. , Vetrie, D. , Holyoake, T. and Jørgensen, H. G. (2022) Tyrosine kinase inhibitor independent gene expression signature in CML offers new targets for LSPC eradication therapy. Cancers, 14(21), 5253. (doi: 10.3390/cancers14215253) (PMID:36358672) (PMCID:PMC9655972)

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Tyrosine kinase inhibitors (TKI) have revolutionised the treatment of CML. However, TKI do not eliminate the leukaemia stem cells (LSC), which can re-initiate the disease. Thus, finding new therapeutic targets in CML LSC is key to finding a curative treatment. Using microarray datasets, we defined a list of 227 genes that were differentially expressed in CML LSC compared to the healthy controls but were not affected by TKI in vitro. Two of them, CD33 and PPIF, are targeted by gemtuzumab–ozogamicin and cyclosporin A, respectively. We treated CML and the control CD34+ cells with either drug with or without imatinib to investigate the therapeutic potential of the TKI-independent gene expression programme. Cyclosporine A, in combination with imatinib, reduced the number of CML CFC compared with non-CML controls, but only at supra-therapeutic concentrations. Gemtuzumab–ozogamicin showed an EC50 of 146 ng/mL, below the plasma peak concentration of 630 ng/mL observed in the AML patients and below the EC50 of 3247 ng/mL observed in the non-CML cells. Interestingly, gemtuzumab–ozogamicin seems to promote cell cycle progression in CML CD34+ cells and demonstrated activation of the RUNX1 pathway in an RNAseq experiment. This suggests that targeting the TKI-independent genes in CML LSC could be exploited for the development of new therapies in CML.

Item Type:Articles
Additional Information:This study was supported by Blood Cancer UK (ref: 11017), the Howat Foundation, Glasgow Experimental Cancer Medicine Centre (funded by Cancer Research UK and the Chief Scientist’s Office, Scotland).
Glasgow Author(s) Enlighten ID:Vetrie, Professor David and Gómez Castañeda, Eduardo and Jorgensen, Dr Heather and Munje, Dr Chinmay and Hopcroft, Dr Lisa and Copland, Professor Mhairi and Holyoake, Professor Tessa and Rogers, Dr Simon
Authors: Gómez-Castañeda, E., Hopcroft, L. E.M., Rogers, S., Munje, C., Bittencourt-Silvestre, J., Copland, M., Vetrie, D., Holyoake, T., and Jørgensen, H. G.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Science and Engineering > School of Computing Science
Journal Name:Cancers
ISSN (Online):2072-6694
Published Online:26 October 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Cancers 14(21):5253
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
164891An investigation of the control of cell division and quiescence in leukaemic versus normal haemopoietic stem and progenitor cellsMhairi CoplandBloodwise (BLOODWIS)11017CS - Paul O'Gorman Leukaemia Research Centre