Genetic landscape of recurrent ASXL1, U2AF1, SF3B1, SRSF2, and EZH2 mutations in 304 Chinese patients with myelodysplastic syndromes

Wu, Lingyun; Song, Lingyun; Xu, Lan; Chang, Chunkang; Xu, Feng; Wu, Dong; He, Qi; Su, Jinpeng; Zhou, Liyu; Xiao, Chen; Zhang, Zheng; Zhao, Yuwu; Chen, Sai‐Juan

doi:10.1007/s13277-015-4305-2

Cited by 44 publications

(38 citation statements)

References 29 publications

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“…Mutations in U2AF1 also occur in the closely related condition AML at a frequency of approximately 4% (18), as well as in lung adenocarcinoma and other cancers (18, 19). U2AF1 mutations are associated with a worse overall survival in MDS patients and a higher risk of transformation to AML (11, 20, 21). U2AF1 mutations almost exclusively occur in 2 highly conserved amino acid positions, S34 and Q157, within the 2 zinc finger domains of the protein (6).…”

Section: Introductionmentioning

confidence: 99%

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

Yip¹,

Steeples²,

Repapi³

et al. 2017

Journal of Clinical Investigation

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Mutations of the splicing factor–encoding gene U2AF1 are frequent in the myelodysplastic syndromes (MDS), a myeloid malignancy, and other cancers. Patients with MDS suffer from peripheral blood cytopenias, including anemia, and an increasing percentage of bone marrow myeloblasts. We studied the impact of the common U2AF1S34F mutation on cellular function and mRNA splicing in the main cell lineages affected in MDS. We demonstrated that U2AF1S34F expression in human hematopoietic progenitors impairs erythroid differentiation and skews granulomonocytic differentiation toward granulocytes. RNA sequencing of erythroid and granulomonocytic colonies revealed that U2AF1S34F induced a higher number of cassette exon splicing events in granulomonocytic cells than in erythroid cells. U2AF1S34F altered mRNA splicing of many transcripts that were expressed in both cell types in a lineage-specific manner. In hematopoietic progenitors, the introduction of isoform changes identified in the U2AF1S34F target genes H2AFY, encoding an H2A histone variant, and STRAP, encoding serine/threonine kinase receptor–associated protein, recapitulated phenotypes associated with U2AF1S34F expression in erythroid and granulomonocytic cells, suggesting a causal link. Furthermore, we showed that isoform modulation of H2AFY and STRAP rescues the erythroid differentiation defect in U2AF1S34F MDS cells, suggesting that splicing modulators could be used therapeutically. These data have critical implications for understanding MDS phenotypic heterogeneity and support the development of therapies targeting splicing abnormalities.

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Section: Introductionmentioning

confidence: 99%

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

Yip¹,

Steeples²,

Repapi³

et al. 2017

Journal of Clinical Investigation

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“…mutations from 10 studies 13,15,16,18,20,[23][24][25][26][27] was 1.60 (95% CI:1.33-1.92, P <0.001); this demonstrated that U2AF1 mutations were a poor factor for longer-term survival in MDS patients. The tendency for OS in patients with and without U2AF1 mutations is shown in Figure 3f for each study.…”

Section: U2af1mentioning

confidence: 86%

“…HRs and 95% CIs for OS and LFS were also extracted from the included studies together with the number of patients which survived every year after diagnosis. If the article provided 19 Wu, 2016 20 Jung, 2016 17 Hwang, 2016 16 Kang, 2015 18 Hong, 2015 15 Kim, 2017 13 Tefferi, 2018 21 Hamilton, 2019 22 Xu, 2017 26 Tefferi, 2017 24 Heuser, 2017 23 Wu, 2013 25 Journal Genes Chromosomes…”

Section: Data Extractionmentioning

confidence: 99%

“…Abnormal karyotypes were encountered significantly more often in patients with than without U2AF1 mutations (49.6% vs. 37.8%, P < 0.05); similarly, patients with abnormal karyotypes were significantly more likely to have U2AF1 mutations (19.3% vs 12.1%, P < 0.05) ( Figure 2). As shown in Figure 3a-d, we analyzed the ORs of OS in MDS patients with U2AF1 mutations in eight studies; 13,[15][16][17][18][19][20][21] summary ORs for OS of 1, 2, 3, and 5 years were 0.76 (95% CI: 0.54-1.09), 0.47 (95% CI: 0.35-0.62, P < 0.001), 0.43 (95% CI: 0.24-0.78, P ¼ 0.006), and 0.37 (95% CI: 0.26-0.51, P < 0.001), respectively. In the case of 3-year OS, high heterogeneity was observed with an I 2 of 64% (P ¼ 0.006).…”

Section: Outcome Of the Meta-analysismentioning

confidence: 99%

“…Some studies showed that U2AF1 mutations had no impact on the outcomes of MDS patients, 13,15,16 while others revealed them to be negative factors in MDS prognosis. [17][18][19][20] Hypomethylating agents such as azacytidine and decitabine have been shown by randomized phase III trials to decrease the risk of leukemic transformation and, in a portion of patients, to improve survival. 7 Thus, hypomethylating therapy (HTM) is considered a conventional treatment for MDS patients, and U2AF1 mutations have been reported to affect the response to HTM.…”

Section: Introductionmentioning

confidence: 99%

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Prognostic significance of U2AF1 mutations in myelodysplastic syndromes: a meta-analysis

Zou

Yang

et al. 2019

J Int Med Res

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Introduction: Although the effects of U2 small nuclear RNA auxiliary factor 1 gene (U2AF1) mutations on the outcomes of patients with myelodysplastic syndromes (MDS) have previously been investigated, their prognostic significance remains controversial. We performed a metaanalysis to investigate the impact of U2AF1 mutations on MDS progression. Methods: Two reviewers independently extracted information such as hazard ratios (HRs) and 95% confidential intervals (CIs) for overall survival (OS) and leukemia-free survival (LFS) as well as the number of surviving patients each year after diagnosis from the included studies. Results: Thirteen studies with a total of 3038 patients were included. The summary odds ratio (OR) for U2AF1 mutations with an OS of 5 years was 0.37, the summary HR for U2AF1 mutations in OS was 1.60, and the summary OR for an OS of 5 years in patients with U2AF1 S34 and U2AF1 Q157 was 3.68. There were no significant differences in leukemia-free survival or hypomethylating therapy response between patients with and without U2AF1 mutations. Conclusion: U2AF1 mutations were associated with poor survival in MDS patients, and patients with U2AF1 Q157 had a worse OS than those with U2AF1 S34 . Our findings suggest that MDS patients with U2AF1 mutations could benefit more from hypomethylation therapy.

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Multidimensional assessment of patient condition and mutational analysis in peripheral blood, as tools to improve outcome prediction in myelodysplastic syndromes: A prospective study of the Spanish MDS group

et al. 2017

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The International Prognostic Scoring System and its revised form (IPSS-R) are the most widely used indices for prognostic assessment of patients with myelodysplastic syndromes (MDS), but can only partially account for the observed variation in patient outcomes. This study aimed to evaluate the relative contribution of patient condition and mutational status in peripheral blood when added to the IPSS-R, for estimating overall survival and the risk of leukemic transformation in patients with MDS. A prospective cohort (2006-2015) of 200 consecutive patients with MDS were included in the study series and categorized according to the IPSS-R. Patients were further stratified according to patient condition (assessed using the multidimensional Lee index for older adults) and genetic mutations (peripheral blood samples screened using next-generation sequencing). The change in likelihood-ratio was tested in Cox models after adding individual covariates. The addition of the Lee index to the IPSS-R significantly improved prediction of overall survival [hazard ratio (HR) 3.02, 95% confidence interval (CI) 1.96-4.66, P < 0.001), and mutational analysis significantly improved prediction of leukemic evolution (HR 2.64, 1.56-4.46, P < 0.001). Non-leukemic death was strongly linked to patient condition (HR 2.71, 1.72-4.25, P < 0.001), but not to IPSS-R score (P = 0.35) or mutational status (P = 0.75). Adjustment for exposure to disease-modifying therapy, evaluated as a time-dependent covariate, had no effect on the proposed model's predictive ability. In conclusion, patient condition, assessed by the multidimensional Lee index and patient mutational status can improve the prediction of clinical outcomes of patients with MDS already stratified by IPSS-R.

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Genetic landscape of recurrent ASXL1, U2AF1, SF3B1, SRSF2, and EZH2 mutations in 304 Chinese patients with myelodysplastic syndromes

Cited by 44 publications

References 29 publications

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes

Prognostic significance of U2AF1 mutations in myelodysplastic syndromes: a meta-analysis

Multidimensional assessment of patient condition and mutational analysis in peripheral blood, as tools to improve outcome prediction in myelodysplastic syndromes: A prospective study of the Spanish MDS group

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