Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome

Zhang, Su Jiang; Rampal, Raajit K.; Manshouri, Taghi; Patel, Jay P.; Mensah, Nana Yaa; Kayserian, Andrew; Hricik, Todd; Heguy, Adriana; Hedvat, Cyrus V.; Gönen, Mithat; Kantarjian, Hagop M.; Levine, Ross L.; Abdel-Wahab, Omar; Verstovšek, Srđan

doi:10.1182/blood-2011-11-390252

Cited by 192 publications

(168 citation statements)

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“…9,[18][19][20]24,25 In general, ASXL1 mutations are also rare in pediatric AML. 26,27 However, this was not seen in GATA2 deficiency patients. The average age of GATA2 deficiency patients with an ASXL1 mutation (35.8 ± 12.8 years old, range, 17-59 years old) was markedly younger than that of other MDS/AML groups, but not significantly different from that of GATA2 deficiency patients without an ASXL1 mutation (34.5±17.0 years old, range 10-78 years old) (ttest, P=0.81) ( Figure 2B).…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 66%

“…34 Among MDS/AML patients, ASXL1 mutations are most commonly found in patients with International Prognostic Scoring System low/intermediate 1 risk or normal cytogenetics. 11,15,19,24,26,35 Cytogenetics from 13 of the GATA2 deficiency patients with ASXL1-mutations showed a 46% incidence of unfavorable cytogenetics: monosomy 7 in two, monosomy 7 and trisomy 8 in two, one translocation t(1;22), and one chromosome 6 monosomy (Table 1, Figure 2A). The two GATA2 deficiency patients with ASXL1 mutations described by Bödör et al also had monosomy 7.…”

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confidence: 99%

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Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o n (Online Supplementary Table S2). The PCR were done with AccuPrime Taq DNA Polymerase High Fidelity (Life Technologies, Grand Island, NY, USA) using the manufacturer's recommended conditions with 30 ng of substrate DNA and 35 amplification cycles, with the following amplification parameters: 94°C for 20 seconds; 58°C for 30 seconds, and 68°C for 60 seconds/kilobase of amplified product. The p.G646Wfs*12insG mutation was verified first by repeating the PCR using two different primer sets (Online Supplementary Table S1: primers 1/4, primers 2/3), then by repeating the reactions with different polymerase enzymes [AccuPrime Pfx (Life Technologies, Grand Island, NY, USA), DreamTaq (Thermo Scientific, Pittsburgh, PA, USA)] using the manufacturers' recommended conditions. PCR products were purified using the QIAquick PCR Purification Kit (QIAGEN Sciences, Germantown, MD, USA) and sequenced using ABI 3130XL and 3730 fluorescence-based sequencers. Sequences were analyzed with MacVector, version 12.0 (MacVector, Inc, Cary, NC, USA). Mutations were confirmed with independent PCR with separate primer sets. Statistical analyses were done with GraphPad Prism, version 5.0 (GraphPad Software, Inc., La Jolla CA, USA). The clinical protocols under which these studies were undertaken were reviewed and approved by the Institutional Review Board of the National Institutes of Health, Clinical Research Center. Patients in this study were enrolled in National Institutes of Health/National Institute of Allergy and Infectious Diseases ClinicalTrials.gov Identifier: NCT00018044, NCT00404560, NCT00001467, and National Cancer Institute ClinicalTrials.gov Identifier: NCT00923364. Results and DiscussionWe screened 48 patients with inherited GATA2 mutations to determine the incidence of somatic ASXL1 mutations. A schematic of the ASXL1 region that was sequenced, which contains ~90% of known ASXL1 mutations (COSMIC, v66 14 ), and the position of the mutations found in this study, are shown in Figure 1A. Sequence variations found in the Database of Single Nucleotide Polymorphisms (dbSNP) were not included as mutations Supplementary Table S3). Somatic ASXL1 mutations were detected in 14/48 (29%) patients with GATA2 deficiency (Table 1). All of these mutations were heterozygous and located within exon 13. The ASXL1 mutations found among GATA2 deficiency patients were similar to mutations previously reported in MDS and AML patients,15 including five independent cases of the most frequently described ASXL1 mutation (p.G646Wfs*12insG). The p.G646Wfs*12insG mutation was previously reported in two cousins with a GATA2 mutation who had developed MDS. 12 However, there has been concern over the validity of this particular mutation, with suggestions that it is a PCR artifact since it occurs immediately 3' to an eight base poly G sequence. 16 We confirmed this mutation by © F e r r a t a S t o r t i F o u n d a t i o nrepeating the PCR at least three times for each positive sample (for patie...

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 66%

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confidence: 99%

Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation

et al. 2013

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“…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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“…[27][28][29] SRSF2 is also frequently mutated in leukemic transformation of myeloproliferative neoplasm. 30 These proteins are part of ribonucleoprotein complexes called spliceosomes and are involved in the splicing of introns during pre-mRNA maturation. They belong to the E/A complexes involved in the recognition of pre-mRNA during the very first steps of splicing, more precisely to the recognition of the polypyrimidine track and the acceptor splice site and also the exon splice enhancer.…”

Section: Sf3b1 Mutationsmentioning

confidence: 99%

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

et al. 2012

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Spliceosome mutations represent a new generation of acquired genetic alterations that affect both myeloid and lymphoid malignancies. A substantial proportion of patients with myelodysplastic syndromes (MDSs) or chronic lymphocytic leukemia (CLL) harbor such mutations, which are often missense in type. Genotype-phenotype associations have been demonstrated for one of these mutations, SF3B1, with ring sideroblasts in MDS and 11q22 deletions in CLL. Spliceosome mutations might result in defective spliceosome assembly, deregulated global mRNA splicing, nuclear-cytoplasm export and altered expression of multiple genes. Such mutations are infrequent in other lymphomas, which instead display a separate group of novel mutations involving genes whose products are believed to affect histone acetylation and methylation and chromatin structure (for example, EZH2 and MLL2). On the other hand, some mutations (for example, NOTCH1) occur in both CLL and other immature and mature lymphoid malignancies. In the current review, we discuss potential mechanisms of cell transformation associated with spliceosome mutations, touch upon the increasing evidence regarding the clonal involvement of hematopoietic stem cells in some cases of otherwise mature lymphoid disorders and summarize recent information on recently described mutations in lymphomas. Leukemia (2012Leukemia ( ) 26, 2027Leukemia ( -2031 doi:10.1038/leu.2012 Keywords: CLL; MDS; mutations; spliceosome INTRODUCTIONIn a series of recently published work, the coding sequences of the DNA obtained from mononuclear cells of the bone marrow of patients with myelodysplastic syndromes (MDSs) were compared with presumably germline DNA (T lymphocytes or buccal swab). [1][2][3] The results have included identification of approximately 10 acquired mutations per patient sample and confirmation of the frequency of previously recognized mutations. 1 More importantly, the particular studies revealed the existence of mutations in genes whose products are involved in controlling the mechanism of splicing of pre-messenger RNA. Such mutations were mutually exclusive and were detected in 45-85% of patients with MDS; 1 the majority constituted missense mutations located in restricted regions of proteins.A similar analysis was conducted in chronic lymphocytic leukemia (CLL) where DNA from tumor cells (CD19 þ and CD5 þ lymphocytes) was compared with that of non-tumor cells (granulocytes or fibroblasts). [4][5][6][7] In addition to genes already known to be mutated in this disease, such as TP53 and ATM, 11 genes were found to be recurrently affected. 4,6 The pathway analyses predicted that these mutations affected DNA damage repair and cell cycle, the Wnt, NOTCH1 and inflammatory/TLR signaling pathways, and, as was the case in MDS, control of splicing mechanisms. 4 The common novel observation, from the above-mentioned studies, in both MDS and CLL, was the identification of mutations in genes whose products are involved in the control of RNA splicing. 8 The involvement of oncogenes in RNA processing h...

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Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome

Cited by 192 publications

References 23 publications

Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation

Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

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