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The Spliceosome: A New Therapeutic Target in Chronic Myeloid Leukaemia.

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.

SUBMITTER: Lebecque B

PROVIDER: S-EPMC9563771 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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The Spliceosome: A New Therapeutic Target in Chronic Myeloid Leukaemia.

Lebecque Benjamin B Bourgne Celine C Munje Chinmay C Berger Juliette J Tassin Thomas T Cony-Makhoul Pascale P Guerci-Bresler Agnès A Johnson-Ansah Hyacinthe H Liu Wei W Saugues Sandrine S Tchirkov Andrei A Vetrie David D Copland Mhairi M Berger Marc G MG

Cancers 20220927 19

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<sup>+</sup>CD15<sup>-</sup> chronic myeloid leukaemia (CML) cells affect, among others, alternative splicing genes, suggesting that ...[more]

PMID: 36230624

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Project description:BACKGROUND: Chronic Myeloid Leukemia (CML) is a malignant pluripotent stem cells disorder of myeloid cells. In CML patients, polymorphonuclear leukocytes (PMNL) the terminally differentiated cells of myeloid series exhibit defects in several actin dependent functions such as adhesion, motility, chemotaxis, agglutination, phagocytosis and microbicidal activities. A definite and global abnormality was observed in stimulation of actin polymerization in CML PMNL. Signalling molecules ras and rhoGTPases regulate spatial and temporal polymerization of actin and thus, a broad range of physiological processes. Therefore, status of these GTPases as well as actin was studied in resting and fMLP stimulated normal and CML PMNL. METHODS: To study expression of GTPases and actin, Western blotting and flow cytometry analysis were done, while spatial expression and colocalization of these proteins were studied by using laser confocal microscopy. To study effect of inhibitors on cell proliferation CCK-8 assay was done. Significance of differences in expression of proteins within the samples and between normal and CML was tested by using Wilcoxon signed rank test and Mann-Whitney test, respectively. Bivariate and partial correlation analyses were done to study relationship between all the parameters. RESULTS: In CML PMNL, actin expression and its architecture were altered and stimulation of actin polymerization was absent. Differences were also observed in expression, organization or stimulation of all the three GTPases in normal and CML PMNL. In normal PMNL, ras was the critical GTPase regulating expression of rhoGTPases and actin and actin polymerization. But in CML PMNL, rhoA took a central place. In accordance with these, treatment with rho/ROCK pathway inhibitors resulted in specific growth inhibition of CML cell lines. CONCLUSIONS: RhoA has emerged as the key molecule responsible for functional defects in CML PMNL and therefore can be used as a therapeutic target in CML.

Dataset Information

The Spliceosome: A New Therapeutic Target in Chronic Myeloid Leukaemia.

Publications

The Spliceosome: A New Therapeutic Target in Chronic Myeloid Leukaemia.

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