Antisense oligonucleotides as a targeted therapeutic approach in model of acute myeloid leukemia.

Autor: Macečková D; Laboratory of Tumor Biology and Immunotherapy, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia. maceckod@lfp.cuni.cz.; Laboratory of Tumor Biology and Immunotherapy Biomedical Center, Faculty of Medicine in Pilsen, Charles University, alej Svobody 76, Pilsen, 32300, Czech Republic. maceckod@lfp.cuni.cz., Vaňková L; Department of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia., Bufka J; Department of Pediatrics, University Hospital Pilsen and Faculty of Medicine in Pilsen, Pilsen, Czechia., Hošek P; Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia., Moravec J; Laboratory of Proteomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia., Pitule P; Laboratory of Tumor Biology and Immunotherapy, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia.; Department of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia.
Jazyk: angličtina
Zdroj: Molecular biology reports [Mol Biol Rep] 2024 Dec 18; Vol. 52 (1), pp. 57. Date of Electronic Publication: 2024 Dec 18.
DOI: 10.1007/s11033-024-10172-w
Abstrakt: Background: The genetic and epigenetic alterations observed in acute myeloid leukemia (AML) contribute to its heterogeneity, influencing disease progression response to therapy, and patient outcomes. The use of antisense oligonucleotides (ASOs) technology allows for the design of oligonucleotide inhibitors based on gene sequence information alone, enabling precise targeting of key molecular pathways or specific genes implicated in AML.
Methods and Results: Midostaurin, a FLT3 specific inhibitor and ASOs targeting particular genes, exons, or mutations was conducted using AML models. This ASOs treatment was designed to bind to exon 7 of the MBNL1 (muscleblind-like) gene. Another target was the FLT3 gene, focusing on two aspects: (a) FLT3-ITD (internal tandem duplication), to inhibit the expression of this aberrant gene form, and (b) the FLT3 in general. Treated and untreated cells were analyzed using quantitative PCR (qPCR), dot blot, and Raman spectroscopy. This study contrasts midostaurin with ASOs that inhibit FLT3 protein production or its isoforms via mRNA degradation. A trend of increased FLT3 expression was observed in midostaurin-treated cells, while ASO-treated cells showed decreased expression, though these changes were not statistically significant.
Conclusions: In AML, exon 7 of MBNL1 is involved in several cellular processes and in this study, exon 7 of MBNL1 was targeted for method optimization, with the highest block of the exon 7 gene variant observed 48 h post-transfection. Midostaurin, a multitargeted kinase inhibitor, acts against the receptor tyrosine kinase FLT3, a critical molecule in AML pathogenesis. While midostaurin blocks FLT3 signaling pathways, it paradoxically increases FLT3 expression.
Competing Interests: Declarations. Ethical approval: Not applicable. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)
Databáze: MEDLINE
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