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Aberrant splicing in B-cell acute lymphoblastic leukemia [cell line]

ABSTRACT: Aberrant splicing in B-cell acute lymphoblastic leukemia [cell line]

PROVIDER: PRJNA475682 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7293830_1.fastq.gz	Fastqsanger.gz
	SRR7293830_2.fastq.gz	Fastqsanger.gz
	SRR7293827_1.fastq.gz	Fastqsanger.gz
	SRR7293827_2.fastq.gz	Fastqsanger.gz
	SRR7293828_1.fastq.gz	Fastqsanger.gz

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Aberrant splicing in B-cell acute lymphoblastic leukemia [cell line]

Project description:Aberrant splicing is a hallmark of leukemias with mutations in splicing factor (SF)-encoding genes. Here we investigated its prevalence in pediatric B-cell acute lymphoblastic leukemias (B-ALL), where SFs are not mutated. By comparing them to normal pro-B cells, we found thousands of aberrant local splice variations (LSVs) per sample, with 279 LSVs in 241 genes present in every comparison. These genes were enriched in RNA processing pathways and encoded ~100 SFs, e.g. hnRNPA1. hnRNPA1 3’UTR was most pervasively misspliced, yielding the transcript subject to nonsense-mediated decay. Thus, we knocked it down in B-lymphoblastoid cells, identified 213 hnRNPA1-dependent splicing events, and defined the hnRNPA1 splicing signature in pediatric leukemias. One of its elements was DICER1, a known tumor suppressor gene; its LSVs involved the 5’ UTR, suggestive of splicing as a mechanism of translational deregulation. Additionally, we searched for LSVs in other leukemia and lymphoma drivers and discovered 81 LSVs in 41 genes. 77 LSVs were confirmed using two large independent B-ALL RNA-seq datasets. In fact, the twenty most common B-ALL drivers showed higher prevalence of aberrant splicing than of somatic mutations. Thus, post-transcriptional deregulation of SF can drive widespread changes in B-ALL splicing and likely contribute to disease pathogenesis.

2018-10-02 | GSE115654 | GEO

Aberrant splicing in B-cell acute lymphoblastic leukemia [B-ALL]

Project description:Aberrant splicing in B-cell acute lymphoblastic leukemia [B-ALL]

| PRJNA475683 | ENA

Aberrant splicing in B-cell acute lymphoblastic leukemia [B-ALL]

2018-10-02 | GSE115653 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia

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.

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Post-transational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_SI_24hr_300bp]

Project description:In this study, we show that pediatric T-cell acute lymphoblastic leukemia (T-ALL) has an alternative mechanism for aberrant splicing that involves post-translational regulation of the splicing machinery via deubiquitination.

2020-06-01 | GSE149624 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_shSRSF6]

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Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [CUTLL1_P5091]

2020-06-01 | GSE139620 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_P5091]

2020-06-01 | GSE139619 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [CUTLL1_H3B-8800]

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Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Patients II]

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