Clinical implications of U2AF1 mutation in patients with myelodysplastic syndrome and its stability during disease progression

Wu, Shang‐Ju; Tang, Jih-Luh; Lin, Chun‐Chi; Kuo, Yueh‐Hsiung; Li, Li-Yu; Tseng, Mei‐Hsuan; Huang, Chih‐Fen; Lai, Yen‐Jun; Lee, Fen‐Yu; Liu, Ming-Chih; Liu, Chia-Wen; Hou, Hsin‐An; Chen, Chien-Yuan; Chou, Wen‐Chien; Yao, Ming; Huang, Shang-Yi; Ko, Bor-Sheng; Tsay, Woei; Tien, Hwei‐Fang

doi:10.1002/ajh.23541

Cited by 56 publications

(61 citation statements)

References 40 publications

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“…In our comprehensive analysis of 511 MDS patients, we identified that mutations involved in the splicing pathway are the most common mutations (37%) in our cohort. Compared with previous studies, U2AF1 MT was slightly more frequent (17%), but SRSF2 mutations were rare (2.3%) and obviously less frequent in this cohort, and the distributions of S34 versus Q157 mutations were also much higher in our cohort. We considered several reasons to explain these differences.…”

Section: Discussioncontrasting

confidence: 87%

Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes

Liu

Jia

et al. 2017

Genes Chromosomes & Cancer

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U2AF1 mutations (U2AF1MT) occur commonly in myelodysplastic syndromes (MDS) without ring sideroblasts. The aim of this study was to investigate the clinical and biological implications of different U2AF1 mutation types in MDS. We performed targeted gene sequencing in a cohort of 511 MDS patients. Eighty-six patients (17%) were found to have U2AF1MT, which occurred more common in younger patients (P = .001) and represented ancestral lesions in a substantial proportion (71%) of cases. ASXL1MT and isolated +8 were significantly enriched in U2AF1MT-positive cases, whereas TP53MT, SF3B1MT, and complex karyotypes were inversely associated with U2AF1MT. U2AF subjects were enriched for isolated +8 and were inversely associated with complex karyotypes. U2AF1MT was significantly associated with anemia, thrombocytopenia, and poor survival in both lower-risk and higher-risk MDS. U2AF1 subjects had more frequently platelet levels of <50 × 10 /L (P = .043) and U2AF1 /U2AF1 subjects had more frequently hemoglobin concentrations at <80 g/L (P = .008) and more often overt fibrosis (P = .049). In conclusion, our study indicates that U2AF1MT is one of the earliest genetic events in MDS patients and that different types of U2AF1MT have distinct clinical and biological characteristics.

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Section: Discussioncontrasting

confidence: 87%

Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes

Liu

Jia

et al. 2017

Genes Chromosomes & Cancer

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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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“…These were missense U2AF1 p.Q157P (c.470A>C) with 23% allele frequency and nonsense DNMT3A p.C368X (c.C1104A) mutations with 21% allele frequency. U2AF1 p.Q157P (c.470A>C) was previously reported in patients with MDS 54,55 and PMF 56 . Interestingly, a daughter of this woman was diagnosed with acute leukemia.…”

Section: Resultsmentioning

confidence: 62%

Characteristics of myeloproliferative neoplasms in patients exposed to ionizing radiation following the Chernobyl nuclear accident

et al. 2018

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Myeloproliferative neoplasms (MPNs) driver mutations are usually found in JAK2, MPL and CALR genes, however, 10–15% of cases are triple negative (TN). A previous study showed lower rate of JAK2 V617F in Primary Myelofibrosis (PMF) patients exposed to low doses of ionizing radiation (IR) from Chernobyl accident. To examine distinct driver mutations, we enrolled 281 Ukrainian IR-exposed and unexposed MPN patients. Genomic DNA was obtained from peripheral blood leukocytes. JAK2 V617F, MPL W515, type 1- and 2-like CALR mutations were identified by Sanger Sequencing and RT-PCR. Chromosomal alterations were assessed by oligo-SNP microarray platform. Additional genetic variants were identified by whole exome and targeted sequencing. Statistical significance was evaluated by Fisher’s exact test and Wilcoxon’s rank sum test (R, version 3.4.2). IR-exposed MPN patients exhibited a different genetic profile versus unexposed: lower rate of JAK2 V617F (58.4% vs 75.4%, P = 0.0077), higher rate of type 1-like CALR mutation (12.2% vs 3.1%, P = 0.0056), higher rate of TN cases (27.8% vs 16.2%, P = 0.0366), higher rate of potentially pathogenic sequence variants (mean numbers: 4.8 vs 3.1, P = 0.0242). Furthermore, we identified several potential drivers specific to IR-exposed TN MPN patients: ATM p.S1691R with copy-neutral loss of heterozygosity at 11q; EZH2 p.D659G at 7q and SUZ12 p.V71M at 17q with copy number loss. Thus, IR-exposed MPN patients represent a group with distinct genomic characteristics worthy of further study.

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Clinical implications of U2AF1 mutation in patients with myelodysplastic syndrome and its stability during disease progression

Cited by 56 publications

References 40 publications

Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes

Clinical features and biological implications of different U2AF1 mutation types in myelodysplastic syndromes

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

Characteristics of myeloproliferative neoplasms in patients exposed to ionizing radiation following the Chernobyl nuclear accident

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