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Alternative Splicing in Myeloid Malignancies.

ABSTRACT: Alternative RNA splicing (AS) is an essential physiologic function that diversifies the human proteome. AS also has a crucial role during cellular development. In fact, perturbations in RNA-splicing have been implicated in the development of several cancers, including myeloid malignancies. Splicing dysfunction can be independent of genetic lesions or appear as a direct consequence of mutations in components of the RNA-splicing machinery, such as in the case of mutations occurring in splicing factor genes (i.e., SF3B1, SRSF2, U2AF1) and their regulators. In addition, cancer cells exhibit marked gene expression alterations, including different usage of AS isoforms, possibly causing tissue-specific effects and perturbations of downstream pathways. This review summarizes several modalities leading to splicing diversity in myeloid malignancies.

SUBMITTER: Gurnari C

PROVIDER: S-EPMC8698609 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Alternative Splicing in Myeloid Malignancies.

Gurnari Carmelo C Pagliuca Simona S Visconte Valeria V

Biomedicines 20211206 12

Alternative RNA splicing (AS) is an essential physiologic function that diversifies the human proteome. AS also has a crucial role during cellular development. In fact, perturbations in RNA-splicing have been implicated in the development of several cancers, including myeloid malignancies. Splicing dysfunction can be independent of genetic lesions or appear as a direct consequence of mutations in components of the RNA-splicing machinery, such as in the case of mutations occurring in splicing fac ...[more]

PMID: 34944660

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Project description:Recent comprehensive genomic studies including single-cell RNA sequencing and characterization have revealed multiple processes by which protein-coding and noncoding RNA processing are dysregulated in many cancers. More specifically, the abnormal regulation of mRNA and precursor mRNA (pre-mRNA) processing, which includes the removal of introns by splicing, is frequently altered in tumors, producing multiple different isoforms and diversifying protein expression. These alterations in RNA processing result in numerous cancer-specific mRNAs and pathogenically spliced events that generate altered levels of normal proteins or proteins with new functions, leading to the activation of oncogenes or the inactivation of tumor suppressor genes. Abnormally spliced pre-mRNAs are also associated with resistance to cancer treatment, and certain cancers are highly sensitive to the pharmacological inhibition of splicing. The discovery of these alterations in RNA processing has not only provided new insights into cancer pathogenesis but identified novel therapeutic vulnerabilities and therapeutic opportunities in targeting these aberrations in various ways (e.g., small molecules, splice-switching oligonucleotides (SSOs), and protein therapies) to modulate alternative RNA splicing or other RNA processing and modification mechanisms. Some of these strategies are currently progressing toward clinical development or are already in clinical trials. Additionally, tumor-specific neoantigens produced from these pathogenically spliced events and other abnormal RNA processes provide a potentially extensive source of tumor-specific therapeutic antigens (TAs) for targeted cancer immunotherapy. Moreover, a better understanding of the molecular mechanisms associated with aberrant RNA processes and the biological impact they play might provide insights into cancer initiation, progression, and metastasis. Our goal is to highlight key alternative RNA splicing and processing mechanisms and their roles in cancer pathophysiology as well as emerging therapeutic alternative splicing targets in cancer, particularly in gastrointestinal (GI) malignancies.

Dataset Information

Alternative Splicing in Myeloid Malignancies.

Publications

Alternative Splicing in Myeloid Malignancies.

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