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[PMID]:28888985
[Au] Autor:Lee HK; Jin J; Kim SI; Kang MJ; Yi EC; Kim JE; Park JB; Kim H; Chung J
[Ad] Endereço:Department of Biomedical Sciences, Seoul National University Graduate School, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute,
[Ti] Título:A point mutation in the heavy chain complementarity-determining region 3 (HCDR3) significantly enhances the specificity of an anti-ROS1 antibody.
[So] Source:Biochem Biophys Res Commun;493(1):325-331, 2017 Nov 04.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The proto-oncogene tyrosine kinase ROS1 plays a key role in carcinogenesis through gene rearrangement to form a fusion protein with other genes, in which the C-terminal intracellular region of ROS1 participates. The possibility of wild type ROS1 overexpression through epigenetic regulation has been proposed. Here, we generated an antibody, 3B20, reactive to the N-terminal region of ROS1 to use it for the detection of wild type ROS1 in cancerous tissues. Using immunoblot and immunoprecipitation analyses, we found that 3B20 also reacted with heat shock proteins (Hsp)70s. Using homology searching, ROS1 and Hsp70s were found to share an identical amino acid sequence: DLGT. Using alanine mutagenesis of ROS1, the epitope was found to harbor this sequence. To modify the idiotope with the aim of selecting more specific antibodies, we introduced random mutations into the heavy chain complementarity-determining region 3 and successfully generated an antibody clone, 3B20-G1K, with a point mutation that only reacted with ROS1 in enzyme-linked immunosorbent assays, and in immunoblot and immunoprecipitation analysis. In immunohistochemical analysis using 3B20-G1K, ROS1 was found to be absent in normal lung tissues and was overexpressed in a case of lung adenocarcinoma.
[Mh] Termos MeSH primário: Adenocarcinoma/imunologia
Anticorpos Monoclonais/genética
Anticorpos Monoclonais/imunologia
Antineoplásicos/imunologia
Proteínas de Arabidopsis/genética
Neoplasias Pulmonares/imunologia
Proteínas Nucleares/genética
[Mh] Termos MeSH secundário: Adenocarcinoma/tratamento farmacológico
Adenocarcinoma/genética
Anticorpos Monoclonais/administração & dosagem
Antineoplásicos/administração & dosagem
Proteínas de Arabidopsis/imunologia
Regiões Determinantes de Complementaridade/genética
Regiões Determinantes de Complementaridade/imunologia
Desenho de Drogas
Sinergismo Farmacológico
Seres Humanos
Cadeias Pesadas de Imunoglobulinas/genética
Cadeias Pesadas de Imunoglobulinas/imunologia
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Pulmonares/genética
Mutagênese Sítio-Dirigida/métodos
Proteínas Nucleares/imunologia
Mutação Puntual/genética
Proto-Oncogenes
Distribuição Tecidual
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents); 0 (Arabidopsis Proteins); 0 (Complementarity Determining Regions); 0 (Immunoglobulin Heavy Chains); 0 (Nuclear Proteins); 0 (ROS1 protein, Arabidopsis)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170911
[St] Status:MEDLINE


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[PMID]:28630119
[Au] Autor:Katayama S; Suzuki M; Yamaoka A; Keleku-Lukwete N; Katsuoka F; Otsuki A; Kure S; Engel JD; Yamamoto M
[Ad] Endereço:Department of Medical Biochemistry.
[Ti] Título:GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis.
[So] Source:Blood;130(7):908-919, 2017 Aug 17.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chromosomal rearrangements between 3q21 and 3q26 induce inappropriate expression by recruiting a -distal hematopoietic enhancer (G2DHE) to the proximity of the gene, leading to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The acquisition of G2DHE by the gene reciprocally deprives this enhancer of 1 of the 2 alleles, resulting in a loss-of-function genetic reduction in abundance. Because haploinsufficiency is strongly associated with MDS and AML, we asked whether misexpression and haploinsufficiency both contributed to the observed leukemogenesis by using a 3q21q26 mouse model that recapitulates the G2DHE-driven misexpression, but in this case, it was coupled to a heterozygous germ line deletion. Of note, the heterozygous deletion promoted the -provoked leukemic transformation, resulting in early onset of leukemia. The 3q21q26 mice suffered from leukemia in which B220 cells and/or Gr1 leukemic cells occupied their bone marrows. We found that the B220 Gr1 c-Kit population contained leukemia-initiating cells and supplied Gr1 leukemia cells in the 3q21q26 leukemia. When expression levels in the B220 Gr1 c-Kit cells were decreased as a result of heterozygous deletion or spontaneous phenomenon, myeloid differentiation of the B220 Gr1 c-Kit cells was suppressed, and the cells acquired induced proliferation as well as B-lymphoid-primed characteristics. Competitive transplantation analysis revealed that heterozygous deletion confers selective advantage to EVI1-expressing leukemia cell expansion in recipient mice. These results demonstrate that both the inappropriate stimulation of and the loss of 1 allele equivalent of expression contribute to the acceleration of leukemogenesis.
[Mh] Termos MeSH primário: Carcinogênese/patologia
Proteínas de Ligação a DNA/metabolismo
Fator de Transcrição GATA2/genética
Haploinsuficiência/genética
Leucemia/patologia
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Alelos
Animais
Carcinogênese/genética
Diferenciação Celular
Proliferação Celular
Cromossomos de Mamíferos/genética
Metabolismo Energético/genética
Regulação Leucêmica da Expressão Gênica
Células-Tronco Hematopoéticas/metabolismo
Leucemia/genética
Proteína do Locus do Complexo MDS1 e EVI1
Camundongos Endogâmicos C57BL
Modelos Biológicos
Transplante de Neoplasias
Células-Tronco Neoplásicas/metabolismo
Células-Tronco Neoplásicas/patologia
Fenótipo
Proteínas Proto-Oncogênicas c-kit/metabolismo
Proto-Oncogenes
Estresse Fisiológico/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (GATA2 Transcription Factor); 0 (MDS1 and EVI1 Complex Locus Protein); 0 (Mecom protein, mouse); 0 (Transcription Factors); EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-12-756767


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[PMID]:28513830
[Au] Autor:Lee DW; Han SW; Cha Y; Bae JM; Kim HP; Lyu J; Han H; Kim H; Jang H; Bang D; Huh I; Park T; Won JK; Jeong SY; Park KJ; Kang GH; Kim TY
[Ad] Endereço:Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
[Ti] Título:Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer.
[So] Source:Cancer;123(18):3513-3523, 2017 Sep 15.
[Is] ISSN:1097-0142
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC. METHODS: Targeted next-generation sequencing of 40 genes included in the 5 critical pathways of CRC (WNT, P53, RTK-RAS, phosphatidylinositol-4,5-bisphosphate 3-kinase [PI3K], and transforming growth factor ß [TGF-ß]) was performed for 516 patients with stage III or high-risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. The associations between critical pathway mutations and relapse-free survival (RFS) and overall survival were analyzed. The associations were further analyzed according to the tumor location. RESULTS: The mutation rates for the WNT, P53, RTK-RAS, PI3K, and TGF-ß pathways were 84.5%, 69.0%, 60.7%, 30.0%, and 28.9%, respectively. A mutation in the PI3K pathway was associated with longer RFS (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36-0.99), whereas a mutation in the RTK-RAS pathway was associated with shorter RFS (adjusted HR, 1.60; 95% CI, 1.01-2.52). Proximal tumors showed a higher mutation rate than distal tumors, and the mutation profile was different according to the tumor location. The mutation rates of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), and B-Raf proto-oncogene serine/threonine kinase (BRAF) were higher in proximal tumors, and the mutation rates of adenomatous polyposis coli (APC), tumor protein 53 (TP53), and neuroblastoma RAS viral oncogene homolog (NRAS) were higher in distal tumors. The better RFS with the PI3K pathway mutation was significant only for proximal tumors, and the worse RFS with the RTK-RAS pathway mutation was significant only for distal tumors. CONCLUSIONS: A PI3K pathway mutation was associated with better RFS for CRC patients treated with adjuvant chemotherapy, and an RTK-RAS pathway mutation was associated with worse RFS. The significance of the prognostic impact differed according to the tumor location. Cancer 2017;123:3513-23. © 2017 American Cancer Society.
[Mh] Termos MeSH primário: Classe I de Fosfatidilinositol 3-Quinases/genética
Neoplasias Colorretais/genética
Neoplasias Colorretais/mortalidade
Regulação Neoplásica da Expressão Gênica
Mutação
Proto-Oncogenes/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Quimioterapia Adjuvante
Estudos de Coortes
Colectomia/métodos
Neoplasias Colorretais/patologia
Neoplasias Colorretais/terapia
Terapia Combinada
Intervalos de Confiança
Procedimentos Clínicos
Feminino
Genes ras
Seres Humanos
Masculino
Meia-Idade
Razão de Chances
Valor Preditivo dos Testes
Prognóstico
Receptor do Fator de Crescimento Epidérmico/genética
República da Coreia
Estudos Retrospectivos
Análise de Sobrevida
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (PIK3CA protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170518
[St] Status:MEDLINE
[do] DOI:10.1002/cncr.30760


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[PMID]:28484159
[Au] Autor:Sato K; Sakai H; Uchida A; Uemura Y; Tsuruoka Y; Yokoi S; Nishio Y; Matsunawa M; Suzuki Y; Isobe Y; Kato M; Tomita N; Inoue Y; Miura I
[Ad] Endereço:Department of Internal Medicine, Division of Hematology and Oncology, St. Marianna University School of Medicine.
[Ti] Título:Acute myeloid leukemia with t (3;8) (q26.2;q24), a simple variant of 3q26.2/EVI1 translocation.
[So] Source:Rinsho Ketsueki;58(4):315-322, 2017.
[Is] ISSN:0485-1439
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo:A 70-year-old man with pancytopenia was referred to our hospital. His bone marrow comprised 75.4% leukemic blast cells and increased micromegakaryocytes. The leukemic cells were positive for myeloperoxidase and expressed CD2, CD13, CD33, CD34, CD56, CD117, HLA-DR, and MYC. Chromosomal analysis revealed 45,XY,t (3;8) (q26.2;q24),-7[6]/46,XY[14]. Fluorescence in situ hybridization revealed the rearrangement of the ecotropic viral integration site 1 (EVI1) gene. Thus, the patient was diagnosed as having acute myeloid leukemia (AML) with maturation, according to the WHO classification; he achieved complete cytogenetic remission after two courses of combination chemotherapy using anthracyclines and cytarabine. The t (3;8) translocation is a rare simple variant of the 3q26.2/EVI1 translocation, which is an adverse prognostic factor of AML. Clarifying the clinical features of leukemia in patients with simple variant translocations facilitates the development of therapies.
[Mh] Termos MeSH primário: Cromossomos Humanos Par 3
Cromossomos Humanos Par 8
Proteínas de Ligação a DNA/genética
Leucemia Mieloide Aguda/genética
Proto-Oncogenes/genética
Fatores de Transcrição/genética
Translocação Genética
[Mh] Termos MeSH secundário: Idoso
Antraciclinas/administração & dosagem
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Citarabina/administração & dosagem
Seres Humanos
Leucemia Mieloide Aguda/tratamento farmacológico
Proteína do Locus do Complexo MDS1 e EVI1
Masculino
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anthracyclines); 0 (DNA-Binding Proteins); 0 (MDS1 and EVI1 Complex Locus Protein); 0 (Mecom protein, mouse); 0 (Transcription Factors); 04079A1RDZ (Cytarabine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170510
[St] Status:MEDLINE
[do] DOI:10.11406/rinketsu.58.315


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[PMID]:28474336
[Au] Autor:Lee S; Day NS; Miles RR; Perkins SL; Lim MS; Ayello J; van de Ven C; Harrison L; El-Mallawany NK; Goldman S; Cairo MS
[Ad] Endereço:Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
[Ti] Título:Comparative genomic expression signatures of signal transduction pathways and targets in paediatric Burkitt lymphoma: a Children's Oncology Group report.
[So] Source:Br J Haematol;177(4):601-611, 2017 May.
[Is] ISSN:1365-2141
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Burkitt lymphoma (BL) is the most common histological subtype of non-Hodgkin lymphoma (NHL) in children and adolescents. Through the introduction of short intensive multi-agent chemoimmunotherapy, survival has improved significantly over the past 30 years. However, this successful approach is limited by significant chemotherapy-induced acute toxicity and risk of developing resistant disease, demonstrating the need to identify less toxic and targeted therapies. We analysed the comparative genomic signature and targetable signalling pathways in paediatric BL (PEBL) samples from the Children's Oncology Group study (ANHL01P1) by genomic profiling and selected genes were confirmed by quantitative real time polymerase chain reaction. These results were compared to PEBL samples from public databases and utilised the Gene Expression Omnibus (GEO) Series (GSE) 10172 and 4475 (n = 16), and 4732 (n = 15). Three hundred and seventy-six genes (approximately 25%) were similarly expressed among three PEBL sample groups. Several target genes in Toll-like receptor signalling, JAK-STAT signalling and MAPK signalling were significantly overexpressed in PEBL. In addition, several tyrosine kinases, including Bruton tyrosine kinase, protein tyrosine phosphatase and histone deacetylase inhibitor were highly expressed in PEBL. These pre-clinical results suggest that specific signal transduction pathways are overly expressed in PEBL and several pathways could serve as potential future therapeutic targets.
[Mh] Termos MeSH primário: Linfoma de Burkitt/genética
Genômica/métodos
Transdução de Sinais/genética
[Mh] Termos MeSH secundário: Adolescente
Criança
Feminino
Expressão Gênica/genética
Perfilação da Expressão Gênica/métodos
Seres Humanos
Lactente
Masculino
Proto-Oncogenes/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170506
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.14604


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[PMID]:28394343
[Au] Autor:Yang J; Liu K; Yang J; Jin B; Chen H; Zhan X; Li Z; Wang L; Shen X; Li M; Yu W; Mao Z
[Ad] Endereço:Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
[Ti] Título:PIM1 induces cellular senescence through phosphorylation of UHRF1 at Ser311.
[So] Source:Oncogene;36(34):4828-4842, 2017 Aug 24.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PIM1 is a proto-oncogene, encoding a serine/threonine protein kinase that regulates cell proliferation, survival, differentiation and apoptosis. Previous reports suggest that overexpression of PIM1 can induce cellular senescence. However, the molecular mechanism underlying this process is not fully understood. Here we report that UHRF1 is a novel substrate of PIM1 kinase, which could be phosphorylated at Ser311 and therefore promoted to degradation. Our data demonstrates that PIM1 destabilizes UHRF1, leading to DNA hypomethylation, which consequently results in genomic instability, increased p16 expression and subsequent induction of cellular senescence. Taken together, our results suggest that down-regulation of UHRF1 is an important mechanism of PIM1-mediated cellular senescence.
[Mh] Termos MeSH primário: Proteínas Estimuladoras de Ligação a CCAAT/metabolismo
Senescência Celular/fisiologia
Fosforilação/fisiologia
Proteínas Proto-Oncogênicas c-pim-1/metabolismo
[Mh] Termos MeSH secundário: Apoptose/fisiologia
Diferenciação Celular/fisiologia
Proliferação Celular/fisiologia
Metilação de DNA/fisiologia
Regulação para Baixo/fisiologia
Instabilidade Genômica/fisiologia
Seres Humanos
Proteínas Serina-Treonina Quinases/metabolismo
Proto-Oncogenes/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCAAT-Enhancer-Binding Proteins); 0 (UHRF1 protein, human); EC 2.7.11.1 (PIM1 protein, human); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-pim-1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170411
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2017.96


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[PMID]:28391050
[Au] Autor:Maicas M; Vázquez I; Alis R; Marcotegui N; Urquiza L; Cortés-Lavaud X; Cristóbal I; García-Sánchez MA; Odero MD
[Ad] Endereço:Program of Hematology-Oncology, CIMA, University of Navarra, Pamplona, Spain; Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain. Electronic address: mmaicas@ibv.csic.es.
[Ti] Título:The MDS and EVI1 complex locus (MECOM) isoforms regulate their own transcription and have different roles in the transformation of hematopoietic stem and progenitor cells.
[So] Source:Biochim Biophys Acta;1860(6):721-729, 2017 06.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Transcriptional activation of the EVI1 oncogene (3q26) leads to aggressive forms of human acute myeloid leukemia (AML). However, the mechanism of EVI1-mediated leukemogenesis has not been fully elucidated. Previously, by characterizing the EVI1 promoter, we have shown that RUNX1 and ELK1 directly regulate EVI1 transcription. Intriguingly, bioinformatic analysis of the EVI1 promoter region identified the presence of several EVI1 potential binding sites. Thus, we hypothesized that EVI1 could bind to these sites regulating its own transcription. In this study, we show that there is a functional interaction between EVI1 and its promoter, and that the different EVI1 isoforms (EVI1-145kDa, EVI1-Δ324 and MDS1-EVI1) regulate the transcription of EVI1 transcripts through distinct promoter regions. Moreover, we determine that the EVI1-145kDa isoform activates EVI1 transcription, whereas EVI1-Δ324 and MDS1-EVI1 act as repressors. Finally, we demonstrate that these EVI1 isoforms are involved in cell transformation; functional experiments show that EVI1-145kDa prolongs the maintenance of hematopoietic stem and progenitor cells; conversely, MDS1-EVI1 repressed hematopoietic stem and progenitor colony replating capacity. We demonstrate for the first time that EVI1 acts as a regulator of its own expression, highlighting the complex regulation of EVI1, and open new directions to better understand the mechanisms of EVI1 overexpressing leukemias.
[Mh] Termos MeSH primário: Transformação Celular Neoplásica/metabolismo
Proteínas de Ligação a DNA/metabolismo
Regulação Leucêmica da Expressão Gênica
Células-Tronco Hematopoéticas/metabolismo
Leucemia/metabolismo
Regiões Promotoras Genéticas
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Transformação Celular Neoplásica/genética
Transformação Celular Neoplásica/patologia
Proteínas de Ligação a DNA/genética
Células-Tronco Hematopoéticas/patologia
Seres Humanos
Leucemia/genética
Leucemia/patologia
Proteína do Locus do Complexo MDS1 e EVI1
Camundongos
Proto-Oncogenes/genética
Fatores de Transcrição/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (MDS1 and EVI1 Complex Locus Protein); 0 (MECOM protein, human); 0 (Mecom protein, mouse); 0 (Transcription Factors)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170410
[St] Status:MEDLINE


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[PMID]:28351939
[Au] Autor:Cooper AR; Lill GR; Shaw K; Carbonaro-Sarracino DA; Davila A; Sokolic R; Candotti F; Pellegrini M; Kohn DB
[Ad] Endereço:Department of Microbiology, Immunology and Molecular Genetics and.
[Ti] Título:Cytoreductive conditioning intensity predicts clonal diversity in ADA-SCID retroviral gene therapy patients.
[So] Source:Blood;129(19):2624-2635, 2017 May 11.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Retroviral gene therapy has proved efficacious for multiple genetic diseases of the hematopoietic system, but roughly half of clinical gene therapy trial protocols using gammaretroviral vectors have reported leukemias in some of the patients treated. In dramatic contrast, 39 adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) patients have been treated with 4 distinct gammaretroviral vectors without oncogenic consequence. We investigated clonal dynamics and diversity in a cohort of 15 ADA-SCID children treated with gammaretroviral vectors and found clear evidence of genotoxicity, indicated by numerous common integration sites near proto-oncogenes and by increased abundance of clones with integrations near and These clones showed stable behavior over multiple years and never expanded to the point of dominance or dysplasia. One patient developed a benign clonal dominance that could not be attributed to insertional mutagenesis and instead likely resulted from expansion of a transduced natural killer clone in response to chronic Epstein-Barr virus viremia. Clonal diversity and T-cell repertoire, measured by vector integration site sequencing and T-cell receptor ß-chain rearrangement sequencing, correlated significantly with the amount of busulfan preconditioning delivered to patients and to CD34 cell dose. These data, in combination with results of other ADA-SCID gene therapy trials, suggest that disease background may be a crucial factor in leukemogenic potential of retroviral gene therapy and underscore the importance of cytoreductive conditioning in this type of gene therapy approach.
[Mh] Termos MeSH primário: Adenosina Desaminase/deficiência
Agamaglobulinemia/genética
Agamaglobulinemia/terapia
Antineoplásicos Alquilantes/uso terapêutico
Bussulfano/uso terapêutico
Gammaretrovirus/genética
Terapia Genética/métodos
Vetores Genéticos/uso terapêutico
Imunodeficiência Combinada Severa/genética
Imunodeficiência Combinada Severa/terapia
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética
Adenosina Desaminase/genética
Agamaglobulinemia/patologia
Criança
Proteínas de Ligação a DNA/genética
Vetores Genéticos/genética
Seres Humanos
Proteínas com Domínio LIM/genética
Proteína do Locus do Complexo MDS1 e EVI1
Proteínas Proto-Oncogênicas/genética
Proto-Oncogenes/genética
Imunodeficiência Combinada Severa/patologia
Linfócitos T/citologia
Linfócitos T/efeitos dos fármacos
Linfócitos T/metabolismo
Linfócitos T/patologia
Fatores de Transcrição/genética
[Pt] Tipo de publicação:CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (Antineoplastic Agents, Alkylating); 0 (DNA-Binding Proteins); 0 (LIM Domain Proteins); 0 (LMO2 protein, human); 0 (MDS1 and EVI1 Complex Locus Protein); 0 (MECOM protein, human); 0 (Proto-Oncogene Proteins); 0 (Transcription Factors); EC 3.5.4.4 (Adenosine Deaminase); G1LN9045DK (Busulfan)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170330
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-12-756734


  9 / 7439 MEDLINE  
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[PMID]:28323522
[Au] Autor:Dogan S; Cilic A; Marjanovic D; Kurtovic-Kozaric A
[Ad] Endereço:a Department of Genetics and Bioengineering , International Burch University , Sarajevo , Bosnia and Herzegovina.
[Ti] Título:Detection of cytosine and CpG density in proto-oncogenes and tumor suppressor genes in promoter sequences of acute myeloid leukemia.
[So] Source:Nucleosides Nucleotides Nucleic Acids;36(4):302-316, 2017 Apr 03.
[Is] ISSN:1532-2335
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aberrant methylation is one of the driving forces of cancer genome development. Although the rate of methylation appears massively variable across the genome, it is mainly observed in histone modification, chromatin organization, DNA accessibility, or promoter sequence. Methylation of promoter sequence occurs mostly to cytosine nucleotides, which can affect transcription factors' binding affinities. In this study, we demonstrated that cytosine repeats (C types density), consisting of CC, CCC, CCCC, CCCCC, CCCCCC, CCCCCCC motifs and CpG islands density in 25 proto-oncogenes, tumor suppressor genes and control genes may play a role in the pathogenesis of acute myeloid leukemia. The promoter sequences were divided into a 100 nucleotide window from -500 to +100 nucleotides and 20 nucleotide window from -100 to +100. Each window is analyzed to find the higher C type and CpG islands density, which may cause the increased methylation in the promoter sequence. Our novel findings show that promoter sequence cytosine repeats and CpG density increase closer to transcription sites, especially just before and after the transcription start site (TSS). The results demonstrate that cytosine density increases while proto-oncogenes and TSG promoter sequences are closer to TSS 50.8% and 41.0% respectively, if (-500 to -200) and (-100 to +100) windows of the nucleotide sequences are compared. This proves that around TSS location has special nucleotide motifs and could be an important implication for our understanding of potential methylating locations in promoters.
[Mh] Termos MeSH primário: Ilhas de CpG/genética
Citosina/metabolismo
Genes Supressores de Tumor
Leucemia Mieloide Aguda/genética
Regiões Promotoras Genéticas/genética
Proto-Oncogenes/genética
[Mh] Termos MeSH secundário: Sequência de Bases
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
8J337D1HZY (Cytosine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE
[do] DOI:10.1080/15257770.2017.1279738


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[PMID]:28259690
[Au] Autor:Jahanban-Esfahlan R; Seidi K; Monfaredan A; Shafie-Irannejad V; Abbasi MM; Karimian A; Yousefi B
[Ad] Endereço:Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
[Ti] Título:The herbal medicine Melissa officinalis extract effects on gene expression of p53, Bcl-2, Her2, VEGF-A and hTERT in human lung, breast and prostate cancer cell lines.
[So] Source:Gene;613:14-19, 2017 May 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Earlier, we verified that Melissa officinalis extract (MOE) elicits potent antiproliferative effects on different human cancer cells. To gain insights into the molecular mechanisms accounting for the cytotoxic effects of MOE, we assessed the expression patterns of several prominent molecules with therapeutic potential in cancer by Quantitative PCR (Q-PCR). METHODS: A549, MCF-7 and PC3 cancer cells were grown in complete RPMI 1640 and seeded in 24 well micro plates. After incubation for 72h, 100µg/ml of MOE was added and the cells were further incubated for 72h. Afterwards, the cells were subjected to RNA extraction for the means of Q-PCR. RESULTS: Our results indicated that in PC3 cancer cells, MOE resulted in a significant downregulation of VEGF-A (0.0004 fold), Bcl-2 (0.001 fold), Her2 (0.02 fold), and hTERT (0.023 fold) compared to the untreated control. In addition, VEGF-A and hTERT mRNA were significantly downregulated in MCF-7 and A549 cancer cells, as well. Notably, high anti-angiogenic activity was closely associated with a high anti-telomerase activity of MOE in studying cancer cells. The decrease in VEGF-A expression was significantly superior than that of hTERT downregulation, as PC3 cancer cells with the highest hTERT down regulation (0.023) presented the highest anti VEGF activity (0.0004 fold), whereas MCF-7 cells with the lowest hTERT inhibition (0.213) showed the lowest VEGF inhibition(0.0435) among the three studied cancer cells. We noticed that the modulation of VEGF-A and hTERT gene expression can be considered as a common target, accounting for the therapeutic potential of MOE on human breast, lung and prostate cancer cells. CONCLUSION: Altogether, it is suggested that the potent antiproliferative activity of the hydroalcoholic extract of Melissa officinalis is somehow explainable by its high potency to inhibit expression of the prominent oncogenes Bcl2, Her2, VEGF-A and hTERT in prostate cancer. In tumors with functional p53, including MCF-7 and A549 cancer cells, the role of p53, Bcl2 and Her2 is less significant. It appears that MOE exerts its antiproliferative effects in these cancer cells partly via concurrent downregulation of VEGF-A and hTERT. Additional studies are needed to clarify the role of other active molecules in cancer cells harboring functional p53.
[Mh] Termos MeSH primário: Antineoplásicos Fitogênicos/farmacologia
Expressão Gênica/efeitos dos fármacos
Melissa/química
Extratos Vegetais/química
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Seres Humanos
Folhas de Planta/química
Proto-Oncogenes/efeitos dos fármacos
Reação em Cadeia da Polimerase em Tempo Real
Proteína Supressora de Tumor p53/genética
Fator A de Crescimento do Endotélio Vascular/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Phytogenic); 0 (Plant Extracts); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170328
[Lr] Data última revisão:
170328
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170306
[St] Status:MEDLINE



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