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

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

PROVIDER: PRJNA818673 | ENA |

REPOSITORIES: ENA

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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]

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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.

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Pharmacologic modulation of RNA splicing enhances anti-tumor immunity.

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Project description:Identification of novel vulnerabilities in the context of therapeutic resistance is emerging as key challenge for cancer treatment. Recent studies have detected pervasive aberrant splicing in cancer cells, supporting its targeting for treatment of hematological malignancies.We here evaluated the expression of several spliceosome machinery components in primary multiple myeloma (MM) cells and the impact of splicing modulations on MM cell growth and viability.Our comprehensive gene expression analysis confirmed deregulation of spliceosome machinery components in MM cells compared to normal plasma cells (PCs) from healthy donors, while pharmacological and genetic modulation of splicing confirmed significant impact on growth and survival of MM cell lines and patient-derived malignant PCs. Transcriptomic analysis revealed deregulation of BCL2 family membersincluding decrease of proapoptotic long form of myeloid cell leukemia-1 (MCL1) expression in cells treated with splicing inhibitors. This caused a shift in the apoptotic priming resulting in improved BCL2-dependenceand increased sensitivity to Venetoclax, a BCL2 small molecule inhibitor, in vitro and in vivo. Overall, our data provide a rationale for supporting clinical use of splicing modulators as strategy to reprogram apoptotic dependencies, making MM patients more vulnerable to BCL2 inhibitors.

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Pharmacologic modulation of RNA splicing enhances anti-tumor immunity.

Project description:Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous antigenicity and clinical potential of such splicing-derived epitopes have not been tested. Here, we demonstrate that pharmacologic modulation of splicing via specific drug classes generates bona fide neoantigens and elicits anti-tumor immunity, augmenting checkpoint immunotherapy. Splicing modulation inhibited tumor growth and enhanced checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Splicing modulation induced stereotyped splicing changes across tumor types, altering the MHC I-bound immunopeptidome to yield splicing-derived neoepitopes that trigger an anti-tumor T cell response in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic.

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Splicing modulation increases BCL2 dependence and sensitizes Multiple Myeloma cells to Venetoclax

Project description:Splicing modulation increases BCL2 dependence and sensitizes Multiple Myeloma cells to Venetoclax

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Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

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AMPK activation enhances apoptotic priming and BCL2 dependence via PERK phosphorylation

Project description:AMPK activation enhances apoptotic priming and BCL2 dependence via PERK phosphorylation

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