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• W4386815747 abstract "Abstract Relapse-specific mutations do not account for all chemotherapy failures in patients with B-cell acute lymphoblastic leukemia (B-ALL). By mining RNA-seq datasets of paired diagnostic/relapse pediatric B-ALL samples, we discovered pervasive aberrant splicing (AS) patterns linked with relapse. They affected drivers of resistance to glucocorticoids, anti-folates, and thiopurines. Most splicing variations represent exon skipping, “poison” exon inclusion, and intron retention, phenocopying well-documented loss-of-function mutations. In addition, relapse-associated AS of NT5C2 mRNA yields an isoform with a cryptic 24-nt in-frame exon 6a. Inclusion of the extra 8 amino acids into this enzyme results in elevated nucleosidase activity, a known consequence of gain-of-function mutations in NT5C2 and a common determinant of 6-mercaptopurine resistance. Furthermore, in B-ALL cells NT5C2ex6a and the R238W hotspot variant confers comparable levels of resistance to 6-mercaptopurine in vitro and in vivo . These results support a role for alternative splicing as a prevalent mechanism driving chemotherapy resistance in relapsed B-ALL. Statement of significance Mutations in chemoresistance genes are found in relapsed/refractory acute lymphoblastic leukemia. However, in this low-mutational-burden disease, up to 30% of cases have no known relapse-specific genetic alterations. Our identification of aberrant splicing as an alternative mechanism of acquired drug resistance fills this gap and suggests new opportunities for therapeutic interventions." @default.
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• W4386815747 date "2023-09-16" @default.
• W4386815747 modified "2023-09-27" @default.
• W4386815747 title "A Novel Aberrantly Spliced Gain-of-Function NT5C2 Isoform Contributes to Thiopurine Resistance in Acute Lymphoblastic Leukemia" @default.
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• W4386815747 doi "https://doi.org/10.1101/2023.09.14.557413" @default.
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