Impact of BCL2 inhibitor Venetoclax on LNCaP cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1142953 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30091640_1.fastq.gz | Fastqsanger.gz | |||
| SRR30091640_2.fastq.gz | Fastqsanger.gz | |||
| SRR30091641_1.fastq.gz | Fastqsanger.gz | |||
| SRR30091641_2.fastq.gz | Fastqsanger.gz | |||
| SRR30091642_1.fastq.gz | Fastqsanger.gz |
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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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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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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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Project description:This SuperSeries is composed of the SubSeries listed below. The translocation t(11;14) occurs in 20% of multiple myeloma (MM) patients and results in the upregulation of CCND1. Nearly two-thirds of t(11;14) MM cells are BCL2 primed and highly responsive to the oral BCL2 inhibitor venetoclax. While it is evident that this unique sensitivity to venetoclax depends on the BH3-proapoptotic protein priming of BCL2, the biology underlying t(11;14) MM dependency on BCL2 is poorly defined. Importantly, the epigenetic regulation of t(11;14) transcriptomes and its impact on gene regulation and clinical response to venetoclax remains elusive. In this study, by integrating ATACseq and RNAseq at the single-cell level in primary MM samples, we have defined the epigenetic regulome and transcriptome associated with t(11;14) MM. A "B cell-like" epigenetic signature was enriched in t(11;14) MM, confirming its phylogeny link to B cell rather than plasma cell biology. Of note, a loss of a "B cell-like" epigenetic signature with a gain of canonical plasma cell transcription factors was observed at the time of resistance to venetoclax. In addition, MCL1 and BCL2L1 copy number gains and structural rearrangements were linked to venetoclax resistance in t(11;14) MM patients. To date, this is the first study in which both scATAC-seq and scRNA-seq analysis are integrated into primary MM cells to obtain a deeper resolution of the epigenetic regulome and transcriptome associated with t(11;14) MM biology and venetoclax resistance.
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Project description:In analyzing transcriptomic data from a clinical trial of neoadjuvant-intensive Androgen Deprivation Therapy, we observed increased mRNA expression of the hallmark antiapoptotic gene BCL2 in the prostate tumors of treated patients versus those of untreated patients. We showed that BCL2 overexpressed LNCaP cells exhibited resistance to prolonged androgen deprivation therapy, indicating that BCL2-overexpression leads to castration resistance and cellular plasticity.Our study indicating that BCL2 overexpression may act as a major driver of early castration resistance in prostate cancer cells.
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Project description:The translocation t(11;14) occurs in 20% of multiple myeloma (MM) patients and results in the upregulation of CCND1. Nearly two-thirds of t(11;14) MM cells are BCL2 primed and highly responsive to the oral BCL2 inhibitor venetoclax. While it is evident that this unique sensitivity to venetoclax depends on the BH3-proapoptotic protein priming of BCL2, the biology underlying t(11;14) MM dependency on BCL2 is poorly defined. Importantly, the epigenetic regulation of t(11;14) transcriptomes and its impact on gene regulation and clinical response to venetoclax remains elusive. In this study, by integrating ATACseq and RNAseq at the single-cell level in primary MM samples, we have defined the epigenetic regulome and transcriptome associated with t(11;14) MM. A "B cell-like" epigenetic signature was enriched in t(11;14) MM, confirming its phylogeny link to B cell rather than plasma cell biology. Of note, a loss of a "B cell-like" epigenetic signature with a gain of canonical plasma cell transcription factors was observed at the time of resistance to venetoclax. In addition, MCL1 and BCL2L1 copy number gains and structural rearrangements were linked to venetoclax resistance in t(11;14) MM patients. To date, this is the first study in which both scATAC-seq and scRNA-seq analysis are integrated into primary MM cells to obtain a deeper resolution of the epigenetic regulome and transcriptome associated with t(11;14) MM biology and venetoclax resistance.
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