Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA371421 | ENA |
REPOSITORIES: ENA
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Project description:H3B-8800, a novel oral splicing modulator, induces lethality in spliceosome mutant cancers
| PRJNA375127 | ENA
Project description:H3B-8800, a novel oral splicing modulator, induces lethality in spliceosome mutant cancers [Nalm-6]
| PRJNA375102 | ENA
Project description:Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factors SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Although cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function, clinical means to therapeutically target the spliceosome do not currently exist. Here, we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and selectively kills spliceosome-mutant epithelial and hematologic malignancies. The effects of H3B-8800 are entirely selective for the Sf3b complex, as evidenced by the identification of drug-resistant cells bearing mutations in Sf3b components. Although H3B-8800 modulates RNA splicing mediated by WT or cancer-associated SF3B1 mutants, its preferential effects on spliceosome-mutant cells is due to preferred retention of short, GC-rich introns, which are enriched in genes encoding a substantial number of spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.
2017-12-20 | GSE94999 | GEO
Project description:Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factors SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Although cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function, clinical means to therapeutically target the spliceosome do not currently exist. Here, we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and selectively kills spliceosome-mutant epithelial and hematologic malignancies. The effects of H3B-8800 are entirely selective for the Sf3b complex, as evidenced by the identification of drug-resistant cells bearing mutations in Sf3b components. Although H3B-8800 modulates RNA splicing mediated by WT or cancer-associated SF3B1 mutants, its preferential effects on spliceosome-mutant cells is due to preferred retention of short, GC-rich introns, which are enriched in genes encoding a substantial number of spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.
2017-12-20 | GSE94528 | GEO
Project description:To study the impact of SF3B1 mutations on alternative splicing and the effect of H3B-8800 splicing modulator in wild type and SF3B1-mutant chronic lymphocytic leukemia cells, we established SF3B1 K700E MEC1 CLL isogenic cell line and carried out RNA deep sequencing in SF3B1 wild type and K700E MEC1 cell lines upon H3B-8800 treatment.
2023-08-08 | GSE190087 | GEO
Project description:Splicing modulation is a promising treatment strategy pursued to date only in splicing-factor mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in cancer and are associated with poor outcomes in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, we show that cohesin mutations are biomarkers of sensitivity to drugs targeting splicing-factor SF3B1 (H3B-8800 and E-7107) and identify drug-induced alterations in splicing of DNA repair genes as the mechanism underlying this sensitivity. We demonstrate that treatment of cohesin-mutant cells with SF3B1 modulators results in impaired DNA damage response, accumulation of DNA damage, and increased sensitivity to a panel of chemotherapeutic agents in vitro and in vivo. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS/AML.
2023-06-30 | GSE198518 | GEO
Project description:Splicing alterations are very common in cancer and might affect disease initiation and progression. In several cancers, mutations in splicing factor genes are responsible for aberrant splicing. We show that certain aggressive cancers, such as pediatric T-cell acute lymphoblastic leukemia (T-ALL), have an alternative mechanism for aberrant splicing that involves post-translational regulation of the splicing machinery via deubiquitination. We initially demonstrated that T-ALL presents with extensive exon skipping events affecting proteasomal transcripts, cell cycle and epigenetic regulators. Performing an unbiased genetic screen study for RNA binding proteins, we showed that the serine/arginine-rich splicing factor (SRSF) proteins, controlling exon skipping are critical for T-ALL survival. In our effort to dissect mechanisms of aberrant regulation of SRSF proteins, we focused on the pro-oncogenic deubiquitinase ubiquitin-specific peptidase 7 (USP7) to show it regulates the levels of the SRSF proteins at the post-translational level via active deubiquitination. We further demonstrated that USP7 inhibitors can change the splicing landscape and block T-ALL growth. Our drug studies show that decrease of the levels of SRSF proteins splicing inhibitors sensitize cells to the clinically used splicing inhibitor H3B-8800. Driven by our molecular findings on aberrant splicing of proteasomal transcripts, we demonstrate that H3B-8800 could act synergistically with proteasome inhibitors, paving the way for new therapeutic schemes in pediatric leukemia. Collectively this study provides the proof-of-principle for regulation of splicing factors independently of mutations and via deubiquitination and suggests new therapeutic modalities and combinations in cancer.
| MSV000084383 | MassIVE
Project description:c-MYC (MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. Like other classic oncogenes, hyperactivation of MYC leads to collateral stresses onto cancer cells, suggesting that tumors harbor unique vulnerabilities arising from oncogenic activation of MYC. Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene, and demonstrate that BUD31 is a splicing factor required for the assembly and catalytic activity of the spliceosome. Core spliceosomal factors (SF3B1, U2AF1, and others) associate with BUD31 and are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total pre-mRNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Importantly, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers. Examination of intron rentention in MYC-ER HMECs, in 4 conditions
2015-09-03 | E-GEOD-66182 | biostudies-arrayexpress
Project description:Mutations in spliceosome genes occur in the bone marrow of approximately 50% of patients with myelodysplastic syndromes (MDS), with mutations in the splicing factor gene U2AF1 found in ~11% of MDS patients. We hypothesized that cells harboring a spliceosome gene mutation would have increased sensitivity to further perturbation of the spliceosome by splicing modulator drugs. To examine the effects of the splicing modulator drug sudemycin D6 on primary hematopoietic cells expressing mutant U2AF1(S34F), we treated transgenic mice expressing either mutant U2AF1(S34F) or U2AF1(wildtype, WT) concurrently with 5 days of sudemycin D6 treatment in vivo. We harvested bulk bone marrow cells 18 hours after the last day of treatment and performed strand-specific transcriptome sequencing to examine the cumulative pre-mRNA splicing changes associated with both mutant U2AF1 expression and sudemycin D6 treatment.
2016-11-15 | GSE89834 | GEO
Project description:The spliceosome is a multimolecular ribonucleoprotein complex, which catalyzes the removal of introns from pre-mRNA and extends the complexity of genetic information by defining alternative transcripts. Here we analyzed the in vivo function of CD2BP2, which is a marker of early spliceosomal complexes. Using gene targeting in mice, we show that constitutive or mesoderm- specific ablation of the CD2BP2 gene causes embryonic lethality by E10.5 associated with delayed development, growth retardation and pericard effusion. Transcriptome analysis in CD2BP2 deficient bone-marrow-derived macrophages (BMM) and podocytes revealed dramatic alterations in the alternative splicing pattern of several mRNAs including VEGFA. Consistent with a previously described critical role of specific VEGFA isoforms for podocyte integrity, mice, which specifically lack CD2BP2flox/flox in this cell type, develop progressive albuminuria followed by lethal kidney failure. We further identified the phosphatase PP1 as a GYF domain independent CD2BP2 interaction partner, suggesting that CD2BP2 acts as an important modulator for spliceosome dephosphorylation, thereby affecting alternative splicing of physiologically highly relevant transcripts.
2016-12-31 | GSE53538 | GEO