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Glucocorticoid resistance in pediatric leukemia is associated with altered splicing profiles and vulnerability to spliceosome modulation

ABSTRACT: Glucocorticoid resistance in pediatric leukemia is associated with altered splicing profiles and vulnerability to spliceosome modulation

PROVIDER: PRJNA551633 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9611090.fastq.gz	Fastqsanger.gz
	SRR9611100.fastq.gz	Fastqsanger.gz
	SRR9611110.fastq.gz	Fastqsanger.gz
	SRR9611120.fastq.gz	Fastqsanger.gz
	SRR9611130.fastq.gz	Fastqsanger.gz

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Glucocorticoid resistance in pediatric leukemia is associated with altered splicing profiles and vulnerability to spliceosome modulation

Project description:The aim of the current study is to characterize the global alternative splicing profiles associated with ex vivo GC resistance in pediatric acute lymphoblastic leukemia (ALL). Specifically, we investigated differential splicing profiles in 38 primary childhood ALL samples by using RNA sequencing. Finally, we tested whether GC-resistant cell lines can be sensitized to GC treatment by using the SF3B modulator Pladienolide-B.

2020-03-24 | GSE133499 | GEO

Glucocorticoid Resistant Pediatric Acute Lymphoblastic Leukemia Samples Display Altered Splicing Profile and Vulnerability to Spliceosome Modulation.

Project description:Glucocorticoid (GC) resistance is a crucial determinant of inferior response to chemotherapy in pediatric acute lymphoblastic leukemia (ALL); however, molecular mechanisms underlying this phenomenon are poorly understood. Deregulated splicing is a common feature of many cancers, which impacts drug response and constitutes an attractive therapeutic target. Therefore, the aim of the current study was to characterize global splicing profiles associated with GC resistance and determine whether splicing modulation could serve as a novel therapeutic option for GC-resistant patients. To this end, 38 primary ALL samples were profiled using RNA-seq-based differential splicing analysis. The impact of splicing modulators was investigated in GC-resistant leukemia cell lines and primary leukemic specimens. Our findings revealed, for the first time, markedly distinct splicing landscapes in ALL samples of B-cell precursor (BCP)-ALL and T-ALL lineages. Differential splicing events associated with GC resistance were involved in RNA processing, a direct response to GCs, survival signaling, apoptosis, cell cycle regulation and energy metabolism. Furthermore, our analyses showed that GC-resistant ALL cell lines and primary samples are sensitive to splicing modulation, alone and in combination with GC. Together, these findings suggest that aberrant splicing is associated with GC resistance and splicing modulators deserve further interest as a novel treatment option for GC-resistant patients.

| S-EPMC7140081 | biostudies-literature

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

Project description:Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma. We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerability in myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.

2020-02-21 | PXD012172 | Pride

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

Project description:Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma (MM). We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerabilityin myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.

2020-02-18 | GSE124510 | GEO

The spliceosome is an exploitable vulnerability in RB1-mutant cancer

Project description:The spliceosome is an exploitable vulnerability in RB1-mutant cancer

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Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

Project description:Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

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HALTING THE NAD+-DEPENDENT DEACETYLASE SIRT6 UNVEILS SPLICEOSOME DEREGULATION AS EXPLOITABLE VULNERABILITY FOR AGGRESSIVE MYELOMA

Project description:Epigenetic defects play a major role in tumors, by promoting aggressiveness, drug resistance and disease progression. Targeting enzymes responsible for these changes holds promise but the knowledge-gap and lack of selective inhibitors severely hampers their clinical use. Recently, we found that Multiple Myeloma (MM) cells exhibit high level of NAD+-dependent deacetylase SIRT6 as an adaptive response to their intrinsic genomic instability. Here we focus on splicing-related events resulting as the most enriched pathways among MM patients with high SIRT6 levels. CoMMpass dataset analysis confirmed the prognostic role of SIRT6 in MM, with its presence correlating with poor outcome and aggressiveness. Transcriptome analysis of SIRT6-depleted MM cells indicated spliceosome perturbation as critical: chemical and genetic approaches resulted in enhanced anti-MM activity of spliceosome modulator Sudamycin D6 (SD6) thus supporting RNA splicing deregulation as vulnerability for these cells. Spliceosome is a therapeutic weakness for MYC-driven cancer, as such we found that while c-MYC oncogene loss shows resistance, its re-expression enhances efficacy of tested strategy. A direct role for SIRT6 on splicing factors genes was also demonstrated using ChIP-seq analyses. Overall, the dysregulated spliceosome activity triggered by epigenetic machinery blocking represents a novel therapeutic strategy for poor-prognosis subset of MM patients overexpressing c-MYC

2022-08-19 | GSE211342 | GEO

Validation of a non-oncogene encoded vulnerability to Exportin 1 inhibition in pediatric renal tumors

Project description:We identified XPO1 as an aberrantly activated, non-oncogene encoded targetable vulnerability in pediatric renal tumors (Wilms and malignant rhabdoid tumor [MRT]) using OncoTarget, a Master Regular-based precision cancer medicine tool. We demonstrate significant anti-tumor activity of selinexor and eltanexor, two selective XPO1 inhibitors, in patient derived xenograft mice models of Wilms and MRT, and report on a case of successful treatment of a pediatric cancer patient.

2022-03-09 | GSE198000 | GEO

PP2A inhibition instructs spliceosome phosphorylation patterns to create splicing vulnerability in colon adenocarcinoma

Project description:PP2A inhibition instructs spliceosome phosphorylation patterns to create splicing vulnerability in colon adenocarcinoma

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Spliceosome iCLIP

Project description:Spliceosome iCLIP

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