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Review
. 2017 May 4;129(18):2465-2470.
doi: 10.1182/blood-2017-02-692715. Epub 2017 Mar 27.

How do messenger RNA splicing alterations drive myelodysplasia?

Poorval Joshi  1 , Stephanie Halene  1 , Omar Abdel-Wahab  2
Affiliations
Review

How do messenger RNA splicing alterations drive myelodysplasia?

Poorval Joshi et al. Blood. .

Abstract

Mutations in RNA splicing factors are the single most common class of genetic alterations in myelodysplastic syndrome (MDS) patients. Although much has been learned about how these mutations affect splicing at a global- and transcript-specific level, critical questions about the role of these mutations in MDS development and maintenance remain. Here we present the questions to be addressed in order to understand the unique enrichment of these mutations in MDS.

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Figures

Figure 1.
Figure 1.
Diagram of the complexes involved in RNA splicing and how trans-acting mutations in splicing factors as well as mutations in sites required for splicing of genes in cis may result in tissue-specific phenotypic effects. The individual steps and components of each spliceosomal complex have been described recently in other reviews.- Germ line mutations in the genes encoding 6 different members of the U4/U6.U5 tri-small nuclear ribonucleoprotein particle (tri-snRNP; red box) result in the retinal degenerative disorder known as autosomal dominant retinitis pigmentosa. Despite the ubiquitous expression of these proteins and their role in core RNA splicing function required in every cell, overt phenotypic effects of these mutations are only apparent within the retina. In contrast to the U4/U6.U5 tri-snRNP mutations in autosomal dominant retinitis pigmentosa, mutations in the RNA splicing factors SF3B1, U2AF1, SRSF2, and ZRSR2 are enriched in leukemias and subsets of epithelial malignancies. Again here, how mutations in core RNA splicing factors expressed in numerous cell types are enriched in diseases of specific lineages remains to be addressed. In addition to mutations in RNA splicing proteins, mutations in coding or noncoding regions are required for RNA splicing of a gene in cis. The earliest examples of such an alteration are the mutations within HBB that are well known to be associated with β-thalassemia. Despite the fact that such mutations may occur in the germ line, the direct phenotypic effects of these mutations are specific to the hematopoietic system given the importance of hemoglobin β to red blood cell function.
Figure 2.
Figure 2.
Requirement of RNA splicing factor mutations in disease initiation vs maintenance. (A) RNA splicing factor mutations are consistently expressed in the presence of the wild-type allele.,, These mutations frequently occur early in the pathogenesis of MDS- and related myeloid neoplasms and are also enriched in clonal hematopoiesis of indeterminate potential,,,, suggesting their role in disease initiation. Consistent with a role in disease initiation, expression of these mutations in the heterozygous state in mice in vivo results in an MDS-like phenotype.- Curiously, however, genetic deletion of the mutant allele appears to have no phenotypic effects in multiple cell types in vitro,,, questioning the role of the mutant allele once a disease is established. In contrast, deletion of the wild-type allele in the setting of expression of the mutant protein is associated with cell lethality.,, (B) Schematic representation of acquisition of RNA splicing factor mutations early in the pathogenesis of clonal hematopoiesis of indeterminate potential and MDS with questions about the role that these mutations at each stage of disease development.
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References

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