The spliceosome: a new therapeutic target in chronic myeloid leukaemia

Lebecque, B. et al. (2022) The spliceosome: a new therapeutic target in chronic myeloid leukaemia. Cancers, 14(19), 4695. (doi: 10.3390/cancers14194695)

Abstract

RNA splicing factors are frequently altered in cancer and can act as both oncoproteins and tumour suppressors. They have been found mutated or deregulated, justifying the growing interest in the targeting of splicing catalysis, splicing regulatory proteins, and/or specific, key altered splicing events. We recently showed that the DNA methylation alterations of CD34+CD15− chronic myeloid leukaemia (CML) cells affect, among others, alternative splicing genes, suggesting that spliceosome actors might be altered in chronic-phase (CP)-CML. We investigated the expression of 12 spliceosome genes known to be oncogenes or tumour suppressor genes in primary CP-CML CD34+ cells at diagnosis (n = 15). We found that CP-CML CD34+ cells had a distinct splicing signature profile as compared with healthy donor CD34+ cells or whole CP-CML cells, suggesting: (i) a spliceosome deregulation from the diagnosis time and (ii) an intraclonal heterogeneity. We could identify three profile types, but there was no relationship with a patient’s characteristics. By incubating cells with TKI and/or a spliceosome-targeted drug (TG003), we showed that CP-CML CD34+ cells are both BCR::ABL and spliceosome dependent, with the combination of the two drugs showing an additive effect while sparing healthy donors cells. Our results suggest that the spliceosome may be a new potential target for the treatment of CML.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Liu, Dr Wei and Munje, Dr Chinmay and Copland, Professor Mhairi and Vetrie, Professor David
• Authors: Lebecque, B., Bourgne, C., Munje, C., Berger, J., Tassin, T., Cony-Makhoul, P., Guerci, A., Johnson-Ansah, H., Liu, W., Saugues, S., Tchirkov, A., Vetrie, D., Copland, M., and Berger, M. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancers
• Publisher: MDPI
• ISSN: 2072-6694
• ISSN (Online): 2072-6694
• Published Online: 27 September 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Cancers 14(19): 4695
• Publisher Policy: Reproduced under a Creative Commons License