Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome

Madan, Vikas; Kanojia, Deepika; Li, Jia; Okamoto, Ryoko; Sato‐Otsubo, Aiko; Kohlmann, Alexander; Sanada, Masashi; Großmann, Vera; Sundaresan, Janani; Shiraishi, Yuichi; Miyano, Satoru; Thol, Felicitas; Ganser, Arnold; Yang, Henry; Haferlach, Torsten; Ogawa, Seishi; Koeffler, H. Phillip

doi:10.1038/ncomms7042

Cited by 212 publications

(275 citation statements)

References 69 publications

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“…ZRSR2 is an essential component of this minor spliceosome. Impaired splicing of the U12-type introns have been observed after shRNA-mediated knockdown of ZRSR2 and in ZRSR2-mutated samples [55]. Recent work [56] suggested that U2 snRNPs components interact with chromatin, independently of RNA.…”

Section: Mutations Of the Sf3b1 Gene And Rna Biologymentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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Recent advances in massively parallel sequencing technologies have provided a detailed picture of the mutational landscape in CLL and underscored the vast degree of interpatient and intratumor heterogeneities. These studies have led to the characterization of novel putative driver genes and recurrently affected biological pathways, and to the modeling of CLL clonal evolution. We herein review selected aspects including recent advances in the biology of CLL and present cellular and biological processes involved in the development of CLL and potentially other mature B-cell lymphoproliferative neoplasms.

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Section: Mutations Of the Sf3b1 Gene And Rna Biologymentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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“…However, the U2AF 35 mutations alter specific ZnK residues, whereas the URP mutations are randomly distributed throughout the protein sequence and often null. This difference most likely reflects the distinct functions of the two proteins: U2AF 35 recognizes the intron-exon junction of the major class of splice sites in conjunction with U2AF 65 (Merendino et al 1999;Wu et al 1999;Zorio and Blumenthal 1999), as opposed to a selective role for URP in a "minor," stress-associated class of intron splicing (Shen et al 2010;Madan et al 2015). Yet, no U2AF 65 paralog has been identified as a ULM partner for the URP UHM to date.…”

Section: Do Uhms Bind Rna?mentioning

confidence: 99%

Unmasking the U2AF homology motif family: a bona fide protein–protein interaction motif in disguise

Loerch

Kielkopf

2016

RNA

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U2AF homology motifs (UHM) that recognize U2AF ligand motifs (ULM) are an emerging family of protein-protein interaction modules. UHM-ULM interactions recur in pre-mRNA splicing factors including U2AF1 and SF3b1, which are frequently mutated in myelodysplastic syndromes. The core topology of the UHM resembles an RNA recognition motif and is often mistakenly classified within this large family. Here, we unmask the charade and review recent discoveries of UHM-ULM modules for protein-protein interactions. Diverse polypeptide extensions and selective phosphorylation of UHM and ULM family members offer new molecular mechanisms for the assembly of specific partners in the early-stage spliceosome.

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“…Puzzling, however, is the observation that mutations in SRSF2 and U2AF1 appear to associate with poor prognosis of the disease while mutations in SF3B1 seem to predict good prognosis (Papaemmanuil et al 2011). ZRSR2 was reported as an essential component of the minor spliceosome (U12 dependent) assembly (Madan et al 2015), which is the least frequent compared to the mutation frequencies of the other three splicing factor genes. As the functions of these splicing factors converge on the definition of 3 ′ splice sites, a popular hypothesis is that mutations in these genes may affect a common set of splicing events that may directly contribute to MDS.…”

Section: Altered Splicing Programs By Splicing Factor Mutations In Mdsmentioning

confidence: 99%

Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators

Qiu

Zhou

Thol

et al. 2016

RNA

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Myelodysplastic syndromes (MDS) are heterogeneous myeloid disorders with prevalent mutations in several splicing factors, but the splicing programs linked to specific mutations or MDS in general remain to be systematically defined. We applied RASL-seq, a sensitive and cost-effective platform, to interrogate 5502 annotated splicing events in 169 samples from MDS patients or healthy individuals. We found that splicing signatures associated with normal hematopoietic lineages are largely related to cell signaling and differentiation programs, whereas MDS-linked signatures are primarily involved in cell cycle control and DNA damage responses. Despite the shared roles of affected splicing factors in the 3 ′ splice site definition, mutations in U2AF1, SRSF2, and SF3B1 affect divergent splicing programs, and interestingly, the affected genes fall into converging cancer-related pathways. A risk score derived from 11 splicing events appears to be independently associated with an MDS prognosis and AML transformation, suggesting potential clinical relevance of altered splicing patterns in MDS.

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Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome

Cited by 212 publications

References 69 publications

Chronic lymphocytic leukemia: Time to go past genomics?

Chronic lymphocytic leukemia: Time to go past genomics?

Unmasking the U2AF homology motif family: a bona fide protein–protein interaction motif in disguise

Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators

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