The clinical implication of SRSF2 mutation in patients with myelodysplastic syndrome and its stability during disease evolution

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

doi:10.1182/blood-2012-02-412296

Cited by 135 publications

(132 citation statements)

References 38 publications

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“…In the report by Qian et al [25], MDS patients with U2AF1 mutation also seemed younger than patients without this mutation, but the difference was not statistically significant. In our prior report, SRSF2 mutation, another spliceosome machinery gene mutation, occurred dominantly in older patients and was associated with male gender and mutations of RUNX1, IDH2, and ASXL1 [17]. Our data indicate that there are distinct clinical and genetic characteristics in MDS with different gene mutations even though the mutations involve the same mRNA-splicing machinery.…”

Section: Discussionmentioning

confidence: 84%

“…These findings suggest that U2AF1 mutation may play a role in the development, but not progression, of MDS. Our prior study showed that SRSF2 mutation was also stable during the disease evolution [17]. These findings suggest that the spliceosome gene mutations, at least SRSF2 and U2AF1 mutations, are more likely a primary hit in MDS development rather than a secondary hit that leads to disease progression.…”

Section: Discussionmentioning

confidence: 96%

“…It is estimated that >90% of human genes undergo alternative splicing and translate into various protein isoforms for different functions, so this splicing process is important for gene expression diversity [12,13]. The clinical implications of mutations involving some of these splicing machinery genes, like SRSF2 [8,11,[14][15][16][17][18] and SF3B1 [8,9,11,14,[19][20][21][22], in MDS patients have been explored. U2AF1 (synonym U2AF35), another splicing machinery gene frequently mutated in MDS [8,10,15,16], belongs to the splicing factor SR family genes and encodes the small subunit of U2 auxiliary factor complex required for the binding of U2 snRNP to the pre-mRNA branch site [23,24].…”

Section: Introductionmentioning

confidence: 99%

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

Tang

Lin

et al. 2013

American J Hematol

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We aimed to analyze clinical impacts of the U2AF1 mutation on patients with myelodysplastic syndrome (MDS) and its stability during disease progression. We checked mutation status of the U2AF1 by direct sequencing in 478 de novo MDS patients and correlated with the clinical characteristics and outcomes. We also sequentially analyzed the U2AF1 mutation in 421 samples from 142 patients to determine its stability during the disease courses. Thirty-six patients (7.5%) were found to have U2AF1 mutations, which occurred more frequently in younger patients (P 5 0.033). U2AF1 mutation was an independent poor-risk factor for overall survival (OS) in all patients (P 5 0.030) and younger patients (P 5 0.041). U2AF1 mutation could also predict shorter time-to-leukemia transformation (TTL) in younger patients (P 5 0.020). In addition, U2AF1 mutation was associated with shorter TTL in lower-risk MDS patients. Sequential analyses showed all original U2AF1 mutations in U2AF1-mutated patients were retained during follow-ups unless complete remission was achieved, whereas none of the U2AF1-wild patients acquired a novel mutation during disease evolution. U2AF1 mutation is more prevalent in younger MDS patients and associated with inferior outcomes although it is stable during the clinical course. The mutation may be used as a biomarker for risk stratification. Am. J. Hematol. 88:E277-E282,

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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

Tang

Lin

et al. 2013

American J Hematol

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“…28 SRSF2 mutations has been described in 47% of chronic myelomonocytic leukemia 29 and, although less frequently, in other types of myelodysplastic and myeloproliferative neoplasms. [30][31][32] All neutrophilic post-polycythemic myelofibrosis cases showed only wild-type alleles for these genes, a finding that suggests that the neutrophilic proliferation arising during the fibrotic stages of polycythemia vera is caused by mechanisms biologically distinct from those involved in chronic neutrophilic leukemia or atypical chronic myeloid leukemia.…”

Section: Modern Pathology (2015) 28 1448-1457mentioning

confidence: 95%

Neutrophilic leukocytosis in advanced stage polycythemia vera: hematopathologic features and prognostic implications

et al. 2015

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“…SRSF2 mutations are seen in patients with MDS, CMML, MPN/PMF, and acute myeloid leukemia (AML) [12,13,16,[18][19][20], and are very rare in juvenile myelomonocytic leukemia [19,21]. In MDS and PMF, SRSF2 mutations are relatively common ( 15-20%) and are associated with shortened OS and LFS [16,18,22]. In CMML, SRSF2 is the most commonly mutated spliceosome gene (28-47%) and has been associated with older age, less pronounced anemia and a diploid karyotype [13,14,19,20].…”

Section: Introductionmentioning

confidence: 99%

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

Patnaik¹,

Lasho²,

Finke³

et al. 2013

American J Hematol

141

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SRSF2, SF3B1, and U2AF35 (U2AF1) are the three most frequent genes involved with spliceosome mutations in myeloid malignancies. SF3B1 mutations are most frequent (~80%) in myelodysplastic syndromes (MDS) with ring sideroblasts (RS) but lack prognostic relevance. SRSF2 mutations are associated with shortened overall (OS) and leukemia-free survival (LFS) in both MDS and myelofibrosis. In this study of 226 patients with chronic myelomonocytic leukemia (CMML), mutational frequencies were 40% for SRSF2 (all affecting P95), 6% for SF3B1 (primarily K700E) and 9% for U2AF35 (mostly S34F and Q157P/R). These mutations were mutually exclusive and 54% of the patients displayed at least one mutation. The three mutation groups were phenotypically similar, with the exception of higher RS% (P < 0.0001) in patients with SF3B1 mutations. At a median follow-up of 15 months, 176 (78%) deaths and 32 (14%) leukemic transformations were documented. OS (median survivals of 17, 16, 17, and 20 months; P 5 0.48) and LFS (leukemic transformation rates of 17, 13, 15, and 5%; P 5 0.63) were similar among patients with none of the three mutations, SRSF2, SF3B1, or U2AF35 mutations, respectively. We conclude that SRSF2 is the most frequently mutated spliceosome gene in CMML but neither it nor SF3B1 or U2AF35 mutations are prognostically relevant. Am. J. Hematol. 88:201-206, 2013. V C 2012 Wiley Periodicals, Inc. IntroductionChronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by features overlapping between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The 2008 World Health Organization (WHO) criteria for diagnosis of CMML include; persistent peripheral blood monocytosis >1 3 10(9)/L, absence of the BCR-ABL1 fusion, absence of rearrangements of the PDGFRA or PDGFRB genes, absence of 20% myeloblasts or promonocytes in the blood and bone marrow (BM), and presence of dysplasia in one or more myeloid lineages [1]. CMML is further subclassified into CMML-1 (<5% circulating blasts and <10% BM blasts) and CMML-2 (5-19% circulating blasts, 10-19% BM blasts, or when Auer rods are present irrespective of the blast count), with the median over-all survival (OS) being 20 and 15 months respectively [1,2].Genetic aberrations are common in CMML and tend to involve different cellular targets and epigenetic regulatory pathways. These include mutations involving; RUNX1 . Thus far, in CMML, loss-of-function mutations involving EZH2 and ASXL1 have been associated with poor outcomes [10,11]. The data with regard to the other mutations needs further elucidation.Mutations in genes of the splicing machinery, such as SF3B1 (splicing factor 3B, subunit 1), SRSF2 (serine/arginine-rich splicing factor 2) and U2AF35, also known as U2AF1 (U2 small nuclear RNA auxiliary factor) are common in patients with myeloid malignancies [12][13][14]. SF3B1 mutations have a high prevalence ( 80%) in MDS and ring sideroblasts (RS) and do not influence either OS or leukemiafree survival (LFS) [15,16]. Similarly, these...

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The clinical implication of SRSF2 mutation in patients with myelodysplastic syndrome and its stability during disease evolution

Cited by 135 publications

References 38 publications

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

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

Neutrophilic leukocytosis in advanced stage polycythemia vera: hematopathologic features and prognostic implications

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: Prevalence, clinical correlates, and prognostic relevance

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