FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1480647923> ?p ?o ?g. }

• W1480647923 endingPage "270" @default.
• W1480647923 startingPage "268" @default.
• W1480647923 abstract "Myeloproliferative neoplasms (MPN), including polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF), are clonal stem cell disorders characterized by an excess of mature cells of one or more myeloid lineages in the chronic phase, and an associated risk of progression to myelofibrosis and leukaemic transformation. Highly specific somatic mutations of JAK2 and MPL are found in the majority of MPN patients, while numerous other somatic mutations have now been identified in common between MPN and de novo acute myeloid leukaemia (AML), including somatic mutations of TET2, ASXL1, CBL, IKZF1, EZH2, IDH1, IDH2 (reviewed in Tefferi, 2010) and most recently the DNA methyltransferase, DNMT3A (Abdel-Wahab et al, 2011; Ley et al, 2011; Stegelmann et al, 2011; Walter et al, 2011; Yan et al, 2011). The overlapping spectrum of mutations highlights common pathways that may interact with aberrant signalling through JAK2 or MPL to induce MPN disease progression, with timing of acquisition directing the disease course. With the aim of investigating the sequence of acquisition and lineage specificity of DNMT3A mutation relative to JAK2 V617F we screened a cohort of MPN patients for mutations within a commonly mutated region of DNMT3A. Approval for the study was obtained from the Royal Adelaide Hospital, The Queen Elizabeth Hospital and Flinders Medical Centre Human Research Ethical Review Committees. A total of 98 patients diagnosed with chronic phase MPN [57 males and 41 females; average age at disease onset, 60 years and 7 months (range, 32–84 years)] were recruited over a period of 11 years from South Australian Hospitals and Haematology Clinics and provided informed written consent and peripheral blood and buccal swab samples. All PV patients were JAK2 V617F or JAK2 exon 12 mutation positive and fulfilled World Health Organization criteria for the diagnosis of PV and patients diagnosed with ET, PMF or unclassified MPN (U-MPN) were screened for the presence of JAK2 V617F. We sequenced the terminal exon of DNMT3A (encoding the methyltransferase domain of the protein; amino acids 866–912) for mutations in genomic DNA isolated from peripheral blood mononuclear cells (PBMNC) of 75 PV, 16 ET, 5 PMF and 2 U-MPN patients. Heterozygous missense variants of DNMT3A affecting amino acids R882 and M880 were detected in PBMNC from two JAK V617F-positive PV patients and were confirmed in granulocyte samples (representing a mutational frequency for this DNMT3A exon of 2·67% in chronic-phase PV). Screening of matched buccal DNA samples indicated that both variants were somatically acquired in these patients (Fig 1). Somatic DNMT3A mutations associated with patients PV113 and PV120. Sequence traces for DNMT3A M880 and R882 and JAK2 V617F allele frequency in genomic DNA isolated from PBMNC, granulocyte and buccal cell populations. Granulocytes and PBMNC were isolated from peripheral blood using standard Dextran T500 sedimentation and density gradient procedures. Mutational screening of the terminal exon of DNMT3A (Genbank # NM_175629.1) was conducted using polymerase chain reaction amplification and bi-directional Sanger sequencing. Primer sequences are available upon request. The JAK2 V617F allele frequency (%) was determined using a single nucleotide primer extension assay as previously described (Butcher et al, 2008). The A to G nucleotide substitution (DNMT3A:c.2638A>G) affecting methionine at position 880 (M880V) is novel and was detected in a 77-year-old male with PV (PV113). This amino acid substitution is predicted to be ‘probably damaging’ by the Polyphen phenotype prediction algorithm and, we suggest, will affect the homodimerization or methyltransferase activity of DNMT3A as reported for R882, however functional studies would be required to investigate this further. The C to T nucleotide substitution (DNMT3A:c.2644C>T), resulting in a R882C substitution, is recurrent in AML (Ley et al, 2011; Yan et al, 2011) and AML secondary to MPN (Stegelmann et al, 2011), and in this study was detected in a 45-year old female with chronic phase PV (PV120). The DNMT3A missense mutations previously reported in AML, MDS and MPN commonly affect this residue, which has been shown to be involved in the homodimerization and functional activation of the protein (Jia et al, 2007). In vitro studies indicate that R882 missense mutations (including R882C) are associated with reduced methyltransferase activity and increased cell proliferation (Yan et al, 2011). In order to further explore the involvement of mutation of DNMT3A in MPN we focused on the known pathogenic R882C mutation and investigated the lineage specificity and timing of acquisition relative to JAK2 V617F in haemopoietic populations isolated from patient PV120. While the DNMT3A R882C mutation was detected at high allele frequency in the CD14+ (monocyte) enriched fraction isolated from patient PV120, the mutation was detected at low frequency in the CD3+ (T lymphocyte), CD19+ (B lymphocyte) enriched fractions, suggesting that the aberrant clone does not penetrate the lymphoid lineage (Fig 2A). This suggests the acquisition of DNMT3A R882C may have occurred in a myeloid lineage-restricted progenitor, or that the DNMT3A or subsequent mutations provide a selective growth advantage in the myeloid rather than lymphoid lineages. Genotyping of individual blast forming units-erythroid (BFU-E) colonies isolated from patient PV120 indicated that the DNMT3A R882C mutation was present in all colonies tested, regardless of the presence of the JAK2 V617F mutation. This is consistent with acquisition of the DNMT3A mutation preceding JAK2 V617F, with subsequent expansion of a single disease clone in this patient (Fig 2B). As somatic mutations of DNMT3A are associated with altered methylation and gene expression profiles in AML (Yan et al, 2011), further studies will be required with large AML and chronic and accelerated-phase MPN cohorts to determine whether DNMT3A-induced changes are important early in the disease process, or whether DNMT3A mutations are acquired in a heterogeneous fashion as reported with other gene mutations in MPN disease progression (Abdel-Wahab, 2011; Schaub et al, 2011). DNMT3A R882C and JAK2 V617F mutation genotyping in haemopoietic lineages. (A) Monocyte (CD14+), T lymphocyte (CD3+) and B lymphocyte (CD19+) enriched populations were isolated from patient PV120 PBMNC by immuno-magnetic bead separation (Miltenyi Biotec, Bergisch Gladbach, Germany). (B) Blast forming units-erythroid (BFU-E) (n = 30) were isolated from patient PV120 as previously described (Butcher et al, 2008). The authors wish to thank the Royal Adelaide Hospital, Queen Elizabeth Hospital and Flinders Medical Centre Haematology Day Centres for valuable assistance with collection of patient samples. This work has been supported by grants from the National Health and Medical Research Council (NH&MRC Project grant #508023) and The Hospital Research Foundation. NR is supported by a Queen Elizabeth Hospital Research Foundation Scholarship. N.R. performed the research, analysed and interpreted data and edited the manuscript; C.B. designed the research study, analysed and interpreted data and wrote the manuscript; I.L. and D.R. contributed and interpreted clinical information and edited the manuscript; J.M. and H.S. edited the manuscript; P.B. contributed and interpreted clinical information; R.D’A designed the research study, analysed and interpreted data and wrote the manuscript." @default.
• W1480647923 created "2016-06-24" @default.
• W1480647923 creator A5021935952 @default.
• W1480647923 creator A5034211889 @default.
• W1480647923 creator A5038779121 @default.
• W1480647923 creator A5040177912 @default.
• W1480647923 creator A5042107262 @default.
• W1480647923 creator A5047899373 @default.
• W1480647923 creator A5048970892 @default.
• W1480647923 creator A5080144419 @default.
• W1480647923 date "2011-08-22" @default.
• W1480647923 modified "2023-10-17" @default.
• W1480647923 title "Clonal and lineage analysis of somatic DNMT3A and JAK2 mutations in a chronic phase polycythemia vera patient" @default.
• W1480647923 cites W1987362547 @default.
• W1480647923 cites W2010318973 @default.
• W1480647923 cites W2020160910 @default.
• W1480647923 cites W2027343725 @default.
• W1480647923 cites W2028803880 @default.
• W1480647923 cites W2066509853 @default.
• W1480647923 cites W2089417246 @default.
• W1480647923 cites W2117206679 @default.
• W1480647923 cites W2131072337 @default.
• W1480647923 cites W2140929811 @default.
• W1480647923 doi "https://doi.org/10.1111/j.1365-2141.2011.08837.x" @default.
• W1480647923 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/21859430" @default.
• W1480647923 hasPublicationYear "2011" @default.
• W1480647923 type Work @default.
• W1480647923 sameAs 1480647923 @default.
• W1480647923 citedByCount "12" @default.
• W1480647923 countsByYear W14806479232012 @default.
• W1480647923 countsByYear W14806479232013 @default.
• W1480647923 countsByYear W14806479232014 @default.
• W1480647923 countsByYear W14806479232015 @default.
• W1480647923 countsByYear W14806479232019 @default.
• W1480647923 countsByYear W14806479232022 @default.
• W1480647923 countsByYear W14806479232023 @default.
• W1480647923 crossrefType "journal-article" @default.
• W1480647923 hasAuthorship W1480647923A5021935952 @default.
• W1480647923 hasAuthorship W1480647923A5034211889 @default.
• W1480647923 hasAuthorship W1480647923A5038779121 @default.
• W1480647923 hasAuthorship W1480647923A5040177912 @default.
• W1480647923 hasAuthorship W1480647923A5042107262 @default.
• W1480647923 hasAuthorship W1480647923A5047899373 @default.
• W1480647923 hasAuthorship W1480647923A5048970892 @default.
• W1480647923 hasAuthorship W1480647923A5080144419 @default.
• W1480647923 hasBestOaLocation W14806479231 @default.
• W1480647923 hasConcept C104317684 @default.
• W1480647923 hasConcept C113968399 @default.
• W1480647923 hasConcept C121608353 @default.
• W1480647923 hasConcept C126322002 @default.
• W1480647923 hasConcept C134305767 @default.
• W1480647923 hasConcept C143998085 @default.
• W1480647923 hasConcept C203014093 @default.
• W1480647923 hasConcept C2776817793 @default.
• W1480647923 hasConcept C2778837598 @default.
• W1480647923 hasConcept C501734568 @default.
• W1480647923 hasConcept C54355233 @default.
• W1480647923 hasConcept C71924100 @default.
• W1480647923 hasConcept C86803240 @default.
• W1480647923 hasConceptScore W1480647923C104317684 @default.
• W1480647923 hasConceptScore W1480647923C113968399 @default.
• W1480647923 hasConceptScore W1480647923C121608353 @default.
• W1480647923 hasConceptScore W1480647923C126322002 @default.
• W1480647923 hasConceptScore W1480647923C134305767 @default.
• W1480647923 hasConceptScore W1480647923C143998085 @default.
• W1480647923 hasConceptScore W1480647923C203014093 @default.
• W1480647923 hasConceptScore W1480647923C2776817793 @default.
• W1480647923 hasConceptScore W1480647923C2778837598 @default.
• W1480647923 hasConceptScore W1480647923C501734568 @default.
• W1480647923 hasConceptScore W1480647923C54355233 @default.
• W1480647923 hasConceptScore W1480647923C71924100 @default.
• W1480647923 hasConceptScore W1480647923C86803240 @default.
• W1480647923 hasIssue "2" @default.
• W1480647923 hasLocation W14806479231 @default.
• W1480647923 hasLocation W14806479232 @default.
• W1480647923 hasOpenAccess W1480647923 @default.
• W1480647923 hasPrimaryLocation W14806479231 @default.
• W1480647923 hasRelatedWork W1506391849 @default.
• W1480647923 hasRelatedWork W2006422832 @default.
• W1480647923 hasRelatedWork W2016712296 @default.
• W1480647923 hasRelatedWork W2044493220 @default.
• W1480647923 hasRelatedWork W2377532759 @default.
• W1480647923 hasRelatedWork W2409651431 @default.
• W1480647923 hasRelatedWork W2525192317 @default.
• W1480647923 hasRelatedWork W2550169079 @default.
• W1480647923 hasRelatedWork W3108028658 @default.
• W1480647923 hasRelatedWork W4280546997 @default.
• W1480647923 hasVolume "156" @default.
• W1480647923 isParatext "false" @default.
• W1480647923 isRetracted "false" @default.
• W1480647923 magId "1480647923" @default.
• W1480647923 workType "article" @default.