Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes

Thol, Felicitas; Kade, Sofia; Schlarmann, Carola; Löffeld, Patrick; Morgan, Michael; Krauter, Jürgen; Wlodarski, Marcin W.; Kölking, Britta; Wichmann, Manfred; Görlich, Kerstin; Göhring, Gudrun; Bug, Gesine; Ottmann, Oliver G.; Niemeyer, Charlotte M.; Hofmann, Wolf‐Karsten; Schlegelberger, Brigitte; Ganser, Arnold; Heuser, Michael

doi:10.1182/blood-2011-12-399337

Cited by 394 publications

(403 citation statements)

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“…Potential targets of miR-575 are the serine/arginine-rich splicing factors SFRS2 (also known as SRSF2) and SFRS1 (also known as SRSF1), which are members of pre-mRNA splicing factors and constitute part of the spliceosome. An SRSF2 mutation is present in ~12% of patients with myelodysplastic syndromes [44][45][46] and frequently mutated in MDS/MPN patients (24%), particularly in CMML (28%) [47]. Although not common in the classic MPNs, SRSF2 mutations are more common in acute myeloid leukemia transformed from MPNs (18.9%) compared with leukemia transformation after myelodysplasia (4.8%) or de novo AML (5.6%) [48].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

Zhan

Cardozo

et al. 2013

Blood Cells, Molecules, and Diseases

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Polycythemia vera (PV) and essential thrombocythemia (ET) are the two most common myeloproliferative neoplasms. The same JAK2 V617F mutation can be found in both disorders and is able to recapitulate many of the phenotypic abnormalities of these diseases in the murine models. The disease phenotype is also influenced by other unknown genetic or epigenetic factors. MicroRNAs (miRNA) are 18-24 nucleotides single-stranded non-protein-coding RNAs that function primarily as gene repressors by binding to their target messenger RNAs. We performed miRNA expression profiling by oligonucleotide microarray analysis in purified peripheral blood CD34+ cells from eight JAK2 V617F -positive PV patients and six healthy donors. A quantitative reverse-transcription polymerase chain reaction assay was used to verify differential miRNA expression. Since erythrocytosis is the only feature that distinguishes PV from ET, we also compared specific miRNA expression in the nucleated erythroid cells directly descended from the early erythroid progenitor cells of PV and ET patients. Our data indicate that significant miRNA deregulation occurs in PV CD34+ cells and confirm a genetic basis for the gender-specific differences that characterize PV with respect to miRNA. The results of our study also suggest that deregulated miRNAs may represent an important mechanism by which the PV erythrocytosis and ET thrombocytosis phenotypes are determined.

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Section: Discussionmentioning

confidence: 99%

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

Zhan

Cardozo

et al. 2013

Blood Cells, Molecules, and Diseases

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“…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 mutations are seen in a small fraction (<10%) of patients with primary myelofibrosis (PMF), are strongly associated with the presence of BM RS, but do not affect disease outcome [17].…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, these mutations are seen in a small fraction (<10%) of patients with primary myelofibrosis (PMF), are strongly associated with the presence of BM RS, but do not affect disease outcome [17]. 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].…”

Section: Introductionmentioning

confidence: 99%

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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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“…3,9 Mutational profiles confer important prognostic information that is independent of other traditional risk factors, including karyotype, blast percentage, and patient clinical characteristics in both acute myeloid leukemia and myelodysplastic syndrome. [10][11][12][13][14][15][16][17][18] The prognostic significance of mutations in therapy-related myeloid neoplasms has not been extensively characterized. Point mutations of the tumor suppressor gene TP53 represent the most frequent single genetic abnormality in therapyrelated myeloid neoplasms and are detected in 20-40% of therapy-related myeloid neoplasm patients compared with 5-20% in de novo acute myeloid leukemia and myelodysplastic syndrome.…”

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High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome

Cleven

Nardi

et al. 2015

Modern Pathology

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Identification of p53-positive cells by immunohistochemistry in bone marrow from primary myelodysplastic syndrome patients correlates with the presence of TP53 mutations and poor prognosis. Mutations in the tumor suppressor gene TP53 are more frequent in therapy-related acute myeloid leukemia and myelodysplastic syndrome than in de novo disease, but the role of p53 immunohistochemistry in the therapy-related setting has not been specifically investigated. We studied p53 protein immunoreactivity in bone marrow biopsies of therapy-related myeloid neoplasms and correlated protein expression with TP53 mutation status, clinicopathologic features and outcome. We first studied 32 patients with therapy-related acute myeloid leukemia and 63 patients with therapy-related myelodysplastic syndrome/chronic myelomonocytic leukemia from one institution and then validated our results in a separate group of 32 patients with therapy-related acute myeloid leukemia and 56 patients with therapy-related myelodysplastic syndrome from a different institution. Strong p53 immunostaining in Z1% of bone marrow cells was highly predictive of a TP53 gene mutation (Po0.0001) and was strongly associated with a high-risk karyotype (Po0.0001). The presence of Z1% p53 strongly positive cells was associated with poorer overall and disease-specific survival, particularly in the subset of patients treated with stem-cell transplantation. In a multivariable Cox regression model, the presence of Z1% p53 strongly expressing cells was an independent prognostic marker for overall survival in both cohorts, with hazard ratios of 3.434 (CI: 1.751-6.735, Po0.0001) and 3.156 (CI: 1.502-6.628, P ¼ 0.002). Our data indicate that p53 protein expression, evaluated in bone marrow biopsies by a widely available immunohistochemical method, prognostically stratifies patients with therapy-related myeloid neoplasms independent of other risk factors. p53 immunostaining thus represents an easily applicable method to assess risk in therapy-related acute myeloid leukemia/myelodysplastic syndrome patients. Therapy-related myeloid neoplasms include acute myeloid leukemia, myelodysplastic syndrome, and less commonly myelodysplastic/myeloproliferative neoplasms such as chronic myelomonocytic leukemia. Therapy-related myeloid neoplasms occur as late complications of cytotoxic chemotherapy and/or radiotherapy given to treat malignancies or non-malignant conditions. 1,2 The etiology of therapy-related myeloid neoplasms is thought to be related to the mutagenic effect of cytotoxic therapy, including alkylating agents, ionizing radiation therapy, and topoisomerase inhibitors. 1 Typically, therapy-related myeloid neoplasms carry complex and usually unbalanced karyotypic abnormalities, particularly loss of material on the long arm of chromosomes 5 and 7 and rearrangements of the 11q23 region involving the MLL gene. 3 The prognosis of therapy-related myeloid neoplasms is poor, likely due at least in part to the high

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Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes

Cited by 394 publications

References 30 publications

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

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

High p53 protein expression in therapy-related myeloid neoplasms is associated with adverse karyotype and poor outcome

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