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

ABSTRACT: H3B-8800, a novel oral splicing modulator, induces lethality in spliceosome mutant cancers

PROVIDER: PRJNA375127 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5230310_1.fastq.gz	Fastqsanger.gz
	SRR5230310_2.fastq.gz	Fastqsanger.gz
	SRR5230311_1.fastq.gz	Fastqsanger.gz
	SRR5230311_2.fastq.gz	Fastqsanger.gz
	SRR5230312_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

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.

2017-12-20 | GSE94528 | GEO

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

2017-12-20 | GSE94999 | GEO

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

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

H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers.

Project description:Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor-encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function, but clinically relevant 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 preferentially kills spliceosome-mutant epithelial and hematologic tumor cells. These killing effects of H3B-8800 are due to its direct interaction with the SF3b complex, as evidenced by loss of H3B-8800 activity in drug-resistant cells bearing mutations in genes encoding SF3b components. Although H3B-8800 modulates WT and mutant spliceosome activity, the preferential killing of spliceosome-mutant cells is due to retention of short, GC-rich introns, which are enriched for genes encoding spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.

| S-EPMC6730556 | biostudies-literature

Investigating the Molecular Mechanism of H3B-8800: A Splicing Modulator Inducing Preferential Lethality in Spliceosome-Mutant Cancers.

Project description:The SF3B1 protein, part of the SF3b complex, recognizes the intron branch point sequence of precursor messenger RNA (pre-mRNA), thus contributing to splicing fidelity. SF3B1 is frequently mutated in cancer and is the target of distinct families of splicing modulators (SMs). Among these, H3B-8800 is of particular interest, as it induces preferential lethality in cancer cells bearing the frequent and highly pathogenic K700E SF3B1 mutation. Despite the potential of H3B-8800 to treat myeloid leukemia and other cancer types hallmarked by SF3B1 mutations, the molecular mechanism underlying its preferential lethality towards spliceosome-mutant cancer cells remains elusive. Here, microsecond-long all-atom simulations addressed the binding/dissociation mechanism of H3B-8800 to wild type and K700E SF3B1-containing SF3b (K700ESB3b) complexes at the atomic level, unlocking that the K700E mutation little affects the thermodynamics and kinetic traits of H3B-8800 binding. This supports the hypothesis that the selectivity of H3B-8800 towards mutant cancer cells is unrelated to its preferential targeting of K700ESB3b. Nevertheless, this set of simulations discloses that the K700E mutation and H3B-8800 binding affect the overall SF3b internal motion, which in turn may influence the way SF3b interacts with other spliceosome components. Finally, we unveil the existence of a putative druggable SF3b pocket in the vicinity of K700E that could be harnessed in future rational drug-discovery efforts to specifically target mutant SF3b.

| S-EPMC8540225 | biostudies-literature

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

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

2017-12-20 | GSE95011 | GEO

Homo sapiens

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

| PRJNA371421 | ENA

Homo sapiens

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

| PRJNA375102 | ENA

T11, AT3, PyMT-M, 2208L GEMM tumors treated with H3B-8800

Project description:T11, AT3, PyMT-M, 2208L GEMM tumors treated with H3B-8800

| PRJNA685157 | ENA

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

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

| PRJNA785817 | ENA

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