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Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199161 | GEO | 2022/10/31

REPOSITORIES: GEO

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Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia.

Project description:Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments.

| S-EPMC9839614 | biostudies-literature

Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia [eCLIP]

Project description:Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR/Cas9 screens across a broad range of therapies used in acute myeloid leukemia (AML) to identify genomic determinants of drug response. Our screens uncovered a selective dependency on RNA splicing factors whose loss preferentially synergized with the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augmented response to venetoclax in leukemia yet was completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition led to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. A novel inhibitor of splicing kinase families CLKs and DYRKs led to intron retention of key splicing factors identified from our screens, synergized with venetoclax, and overcame resistance to BCL2 inhibition. Our findings underscore the central importance of splicing in modulating apoptosis and provide a strategy to improve venetoclax-based treatments.

2022-10-31 | GSE199160 | GEO

Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia [RNA-seq]

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Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia

Project description:Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia

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Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia [eCLIP]

Project description:Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia [eCLIP]

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Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia [RNA-seq]

Project description:Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia [RNA-seq]

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