Splicing factor gene mutations in hematologic malignancies

Sáez, Borja; Walter, Matthew J.; Graubert, Timothy A.

doi:10.1182/blood-2016-10-692400

Cited by 108 publications

(117 citation statements)

References 117 publications

(131 reference statements)

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“…Mutations lie within hotspots (codons 662, 666, 700, 704, 742), with codon 700 harbouring 50% of the mutations, and affect the C‐terminal HEAT‐repeat region of the protein. SF3B1 mutations promote the use of alternative branch point based on their greater (with respect to the regular ones) complementarity to the U2 snRNA, leading to the inclusion of 3′ intronic sequences in the mature RNA (Darman et al , ; Alsafadi et al , ; Kesarwani et al , ; Saez et al , ). It was suggested that SF3B1 mutations increase NOTCH signalling via alternative splicing of a negative regulator of NOTCH signalling, DVL2 (Wang et al , ).…”

Section: Mutations Affecting the Rna Processing Pathwaymentioning

confidence: 99%

Chronic lymphocytic leukaemia genomics and the precision medicine era

2017

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Massive genomic analyses have underscored the diversity of chronic lymphocytic leukaemia (CLL) between patients. Genetic heterogeneity of tumour clones within a patient may fuel tumour evolution. Several recurrently deregulated intra-cellular pathways are candidates for targeted therapies that are very promising and are dramatically changing clinical patients' perspectives. In this review we present an overview of the genetic and epigenetic features of CLL and their clinical and biological implications.

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Section: Mutations Affecting the Rna Processing Pathwaymentioning

confidence: 99%

Chronic lymphocytic leukaemia genomics and the precision medicine era

2017

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“…RNA binding proteins (RBPs) interact with their target RNAs to affect the creation, localization, and function of each RNA molecule in the cell . Disruption of these protein–RNA interactions by mutations in RBPs has been implicated in many diseases including neurodegeneration and cancer . Therefore, identifying the RNA targets of specific RBPs is important for deciphering the molecular mechanisms of RBP‐mediated diseases.…”

Section: Introductionmentioning

confidence: 99%

Advances and challenges in the detection of transcriptome‐wide protein–RNA interactions

2017

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RNA binding proteins (RBPs) play key roles in determining cellular behavior by manipulating the processing of target RNAs. Robust methods are required to detect the numerous binding sites of RBPs across the transcriptome. RNA‐immunoprecipitation followed by sequencing (RIP‐seq) and crosslinking followed by immunoprecipitation and sequencing (CLIP‐seq) are state‐of‐the‐art methods used to identify the RNA targets and specific binding sites of RBPs. Historically, CLIP methods have been confounded with challenges such as the requirement for tens of millions of cells per experiment, low RNA yields resulting in libraries that contain a high number of polymerase chain reaction duplicated reads, and technical inconveniences such as radioactive labeling of RNAs. However, recent improvements in the recovery of bound RNAs and the efficiency of converting isolated RNAs into a library for sequencing have enhanced our ability to perform the experiment at scale, from less starting material than has previously been possible, and resulting in high quality datasets for the confident identification of protein binding sites. These, along with additional improvements to protein capture, removal of nonspecific signals, and methods to isolate noncanonical RBP targets have revolutionized the study of RNA processing regulation, and reveal a promising future for mapping the human protein‐RNA regulatory network. WIREs RNA 2018, 9:e1436. doi: 10.1002/wrna.1436This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA RecognitionRNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional ImplicationsRNA Methods > RNA Analyses in Cells

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“…8, [23][24][25] Although there have been major advances in understanding the role of RNA splicing factor mutations in MDS pathogenesis and therapy (as reviewed recently [26][27][28] ), major questions about their biological consequences within cells, requirement in disease initiation vs maintenance, and cell autonomous vs nonautonomous roles remain. In addition, numerous questions about the structural and biochemical effects of the mutations on protein-protein and protein-RNA interactions.…”

Section: Introductionmentioning

confidence: 99%

How do messenger RNA splicing alterations drive myelodysplasia?

Joshi

Halene

Abdel-Wahab

2017

Blood

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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. (Blood. 2017; 129(18):2465-2470 IntroductionMyelodysplastic syndromes (MDSs) represent clonal disorders of hematopoietic stem cells (HSCs) whereby hematopoietic cell-intrinsic genetic alterations as well as non-cell autonomous factors contribute to an aberrant HSC that produces morphologically abnormal progeny and has impaired ability to generate mature blood cells. Due to the wide clinical and morphologic heterogeneity of MDS, substantial effort has been placed on characterizing the genetic alterations present in MDS cells in hopes of improving our ability to understand, diagnose, and treat the disease. Extensive targeted mutational analysis of protein coding genes has identified that MDS is characterized by a high frequency of mutations in genes encoding messenger RNA (mRNA) splicing factors as well as epigenetic modifiers.1-3 The discovery of mutations in RNA splicing factors in particular was quite unexpected as these mutations are generally uncommon in cancer yet are present in 50% to 60% of MDS patients. Interestingly, there are clear associations between specific mutated splicing factors and subtypes of MDS, most notably mutations in the RNA splicing factor SF3B1 in .90% of patients with MDS with ring sideroblasts.1,2,4 Moreover, the nature of these mutations is quite conspicuous as they occur as heterozygous point mutations at highly recurrent residues. Finally, within MDS patients, these mutations are almost always mutually exclusive; an MDS patient almost never has .1 RNA splicing factor mutation at the same time [1][2][3] (although rare individuals with mutations in .1 RNA splicing factor have been noted, 5 these occur far less frequently than expected by chance in MDS and it is unclear if both mutations in such cases are present within the same cell and/or how the mutations may impact splicing if coexpressed in the same cell).The discovery of RNA splicing factor mutations has led to intense efforts to understand their biological impact on hematopoiesis, 6-9 their genomic and biochemical effects on RNA splicing, 10-21 their structural effects, 22 and potential means to therapeutically target cells bearing these mutations. 8,[23][24][25] Although there have been major advances in understanding the role of RNA splicing factor mutations in MDS pathogenesis and therapy (as reviewed recently [26][27][28] ), major questions about their biological consequences within cells, requirement in disease initiation vs maintenance, and cell autonomous vs nonautonomous roles remain. In addition, numerous questions about the structural and biochemical effects of...

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Splicing factor gene mutations in hematologic malignancies

Cited by 108 publications

References 117 publications

Chronic lymphocytic leukaemia genomics and the precision medicine era

Chronic lymphocytic leukaemia genomics and the precision medicine era

Advances and challenges in the detection of transcriptome‐wide protein–RNA interactions

How do messenger RNA splicing alterations drive myelodysplasia?

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