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Chronic Lymphocytic Leukemia MEC1 SF3B1 K700E and Wild Type Cell Lines' RNA-seq after Treatment with H3B-8800 Splicing Modulator.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190087 | GEO | 2023/08/08

REPOSITORIES: GEO

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H3B-8800, a novel oral splicing modulator, induces lethality in spliceosome mutant cancers [K562]

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.

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H3B-8800, a novel oral splicing modulator, induces lethality in spliceosome mutant cancers [Nalm-6]

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Chronic Lymphocytic Leukemia MEC1 SF3B1 K700E and Wild Type Cell Lines' RNA-seq after Treatment with H3B-8800 Splicing Modulator.

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Transcriptome analysis of SF3B1-mutation induced changes in K562 cells

Project description:Using RNA-Seq, we determined changes to gene expression and splicing on inducible expression of SF3B1-WT and SF3B1-MUT (K700E) in K562 cells. Using RNA-Seq, we determined changes to gene expression and splicing on inducible expression of SF3B1-WT and SF3B1-MUT (K700E) in K562 cells.

2016-07-15 | E-GEOD-70959 | biostudies-arrayexpress

Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs

Project description:SF3B1 K700E is the most frequent mutation in myelodysplastic syndrome (MDS), but the mechanisms by which it drives MDS pathogenesis remain unclear. We derived a panel of 18 genetically matched SF3B1 K700E- and SF3B1 WT-induced pluripotent stem cell (iPSC) lines from patients with MDS with ring sideroblasts (MDS-RS) harboring isolated SF3B1 K700E mutations and performed RNA and ATAC sequencing in purified CD34+/CD45+ hematopoietic stem/progenitor cells (HSPCs) derived from them. We developed a novel computational framework integrating splicing with transcript usage and gene expression analyses and derived a SF3B1 K700E splicing signature consisting of 59 splicing events linked to 34 genes, which associates with the SF3B1 mutational status of primary MDS patient cells. The chromatin landscape of SF3B1 K700E HSPCs showed increased priming toward the megakaryocyte- erythroid lineage. Transcription factor motifs enriched in chromatin regions more accessible in SF3B1 K700E cells included, unexpectedly, motifs of the TEAD family. TEAD expression and transcriptional activity were upregulated in SF3B1-mutant iPSC-HSPCs, in support of a Hippo pathway-independent role of TEAD as a potential novel transcriptional regulator of SF3B1 K700E cells. This study provides a comprehensive characterization of the transcriptional and chromatin landscape of SF3B1 K700E HSPCs and nominates novel mis-spliced genes and transcriptional programs with putative roles in MDS-RS disease biology.

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