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

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 oligonucleotide (AONs) technology allows 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, an FLT3 -specific inhibitor and AONs targeting specific genes, exons, or mutations were evaluated using AML models. This AON treatment was designed to bind to exon 7 of the muscleblind-like ( MBNL1 ) 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 and (b) the FLT3 in general. Treated and untreated cells were analyzed using quantitative PCR, dot blotting, and Raman spectroscopy. This study compared midostaurin with AONs, which inhibit FLT3 protein production or its isoforms via mRNA degradation. Increased FLT3 expression was observed in midostaurin-treated cells, whereas AON-treated cells showed decreased expression; however, these changes were not statistically significant. Conclusions In AML, exon 7 of MBNL1 is involved in several cellular processes. 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 multi-targeted kinase inhibitor, acts against the receptor tyrosine kinase FLT3 , a critical molecule in AML pathogenesis. While midostaurin blocks the FLT3 signaling pathway, it paradoxically increases FLT3 expression.