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Targeting an RNA-binding Protein Splicing Network in Acute Myeloid Leukemia

ABSTRACT: Targeting an RNA-binding Protein Splicing Network in Acute Myeloid Leukemia

PROVIDER: PRJNA471804 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7175410_1.fastq.gz	Fastqsanger.gz
	SRR7175410_2.fastq.gz	Fastqsanger.gz
	SRR7175420_1.fastq.gz	Fastqsanger.gz
	SRR7175420_2.fastq.gz	Fastqsanger.gz
	SRR7175430_1.fastq.gz	Fastqsanger.gz

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Targeting an RNA-binding Protein Splicing Network in Acute Myeloid Leukemia

Project description:RNA-binding proteins (RBPs) are essential modulators of transcription and translation and are often dysregulated in cancer. Here we systematically interrogated RBP vulnerabilities in acute myeloid leukemia (AML) by performing a comprehensive CRISPR/Cas9 screen, targeting the RNA-binding domains of all classical RBPs. Our screen revealed RBPs that are exclusively required for leukemia survival, including the splicing factor RBM39. Proteomics analysis identified a network of RBP’s interacting with RBM39 crucial for maintaining RNA splicing and survival in AML. Mechanistically, RBM39 suppression led to altered splicing of genes involved in essential oncogenic pathways. Selective targeting of RBM39 via ubiquitin-mediated pharmacologic degradation induced broad anti-leukemic effects in vitro and potent single agent activity in vivo. The effects of RBM39 loss on alteration of splicing further resulted in preferential lethality of AML cells bearing spliceosomal gene mutations, thereby providing a strategy for treating AML patients bearing RBP splicing mutations.

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Project description:Acute Myeloid Leukemia (AML) has been associated with somatic mutations in numerous genes; however, the penetrance of these mutations is low. Here we investigate the contribution of alternative splicing as an additional layer of gene dysregulation in AML. By analyzing splicing variations across two patient datasets, we find a consistent set of splicing events that disrupt the coding potential of a subset of AML-associated genes. Importantly, most of these splicing variations are independent of any currently-identified somatic mutations. We have further validated that for EZH2 and ZRSR2 these splicing events reduce the expression of full-length protein. Together these results highlight the contribution of splicing to gene dysregulation and demonstrate that mutation analysis underestimates the burden of functional gene disruption in patient populations.

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Project description:Alternative mRNA splicing represents an effective mechanism of regulating gene function and is a key element to increase the coding capacity of the human genome. Today, an increasing number of reports illustrates that aberrant splicing events are common and functionally important for cancer development. However, more comprehensive analyses are warranted to get novel insights into the biology underlying malignancies like e.g. acute myeloid leukemia (AML). Here, we performed a genome-wide screening of splicing events in AML using an exon microarray platform. We analyzed complex karyotype and core binding factor (CBF) AML cases (n=64) in order to evaluate the ability to detect alternative splicing events distinguishing distinct leukemia subgroups. Testing different commercial and open source software tools to compare the respective AML subgroups, we could identify a large number of potentially alternatively spliced transcripts with a certain overlap of the different approaches. Selected candidates were further investigated by PCR and sequence analysis: out of 24 candidate genes studied, we could confirm alternative splice forms in 8 genes of potential pathogenic relevance, such as PRMT1 regulating transcription through histone methylation and participating in DNA damage response, and PTPN6, which encodes for a negative regulator of cell cycle control and apoptosis. In summary, this first large Exon microarray based study demonstrates that transcriptome splicing analysis in AML is feasible but challenging, in particular with regard to the currently available software solutions. Nevertheless, our results show that alternatively spliced candidate genes can be detected, and we provide a guide how to approach such analyses. Exon expression analysis was performed using GeneChip Human Exon 1.0 ST microarrays in 64 AML patients.

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