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[PMID]: 27776339 [Au] Autor: Jahn L; van der Steen DM; Hagedoorn RS; Hombrink P; Kester MG; Schoonakker MP; de Ridder D; van Veelen PA; Falkenburg JH; Heemskerk MH [Ad] Endereço: Department of Hematology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. [Ti] Título: Generation of CD20-specific TCRs for TCR gene therapy of CD20low B-cell malignancies insusceptible to CD20-targeting antibodies. [So] Source: Oncotarget;7(47):77021-77037, 2016 Nov 22. [Is] ISSN: 1949-2553 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Immunotherapy of B-cell leukemia and lymphoma with CD20-targeting monoclonal antibodies (mAbs) has demonstrated clinical efficacy. However, the emergence of unresponsive disease due to low or absent cell surface CD20 urges the need to develop additional strategies. In contrast to mAbs, T-cells via their T-cell receptor (TCR) can recognize not only extracellular but also intracellular antigens in the context of HLA molecules. We hypothesized that T-cells equipped with high affinity CD20-targeting TCRs would be able to recognize B-cell malignancies even in the absence of extracellular CD20. We isolated CD8+ T-cell clones binding to peptide-MHC-tetramers composed of HLA-A*02:01 and CD20-derived peptide SLFLGILSV (CD20SLF) from HLA-A*02:01neg healthy individuals to overcome tolerance towards self-antigens such as CD20. High avidity T-cell clones were identified that readily recognized and lysed primary HLA-A2pos B-cell leukemia and lymphoma in the absence of reactivity against CD20-negative but HLA-A2pos healthy hematopoietic and nonhematopoietic cells. The T-cell clone with highest avidity efficiently lysed malignant cell-lines that had insufficient extracellular CD20 to be targeted by CD20 mAbs. Transfer of this TCR installed potent CD20-specificity onto recipient T-cells and led to lysis of CD20low malignant cell-lines. Moreover, our approach facilitates the generation of an off-the-shelf TCR library with broad applicability by targeting various HLA alleles. Using the same methodology, we isolated a T-cell clone that efficiently lysed primary HLA-B*07:02pos B-cell malignancies by targeting another CD20-derived peptide. TCR gene transfer of high affinity CD20-specific TCRs can be a valuable addition to current treatment options for patients suffering from CD20low B-cell malignancies. [Mh] Termos MeSH primário: Antígenos CD20/genética Leucemia de Células B/terapia Linfoma de Células B/terapia Receptores de Antígenos de Linfócitos T/genética [Mh] Termos MeSH secundário: Antígenos CD20/imunologia Antígenos CD20/metabolismo Linfócitos T CD8-Positivos/imunologia Terapia Genética Antígeno HLA-A2/imunologia Seres Humanos Células K562 Leucemia de Células B/genética Leucemia de Células B/imunologia Linfoma de Células B/genética Linfoma de Células B/imunologia Receptores de Antígenos de Linfócitos T/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, CD20); 0 (HLA-A2 Antigen); 0 (Receptors, Antigen, T-Cell) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180212 [Lr] Data última revisão: 180212 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161025 [St] Status: MEDLINE [do] DOI: 10.18632/oncotarget.12778

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[PMID]: 28467276 [Au] Autor: Barrell EA; Asakawa MG; Felippe MJB; Divers TJ; Stokol T [Ad] Endereço: Departments of Clinical Sciences, Cornell University, Ithaca, NY (Barrell, Felippe, Divers), College of Veterinary Medicine, Cornell University, Ithaca, NY. [Ti] Título: Acute leukemia in six horses (1990-2012). [So] Source: J Vet Diagn Invest;29(4):529-535, 2017 Jul. [Is] ISSN: 1943-4936 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Acute leukemia is rare in horses. Herein we describe historical, clinicopathologic, and postmortem findings in 6 horses with acute leukemia. Medical records of horses with >20% bone marrow blasts and cytochemical or immunophenotyping results were reviewed. Affected horses were 2-8 y of age and of different breeds and sex. Horses were presented acutely with nonspecific signs (e.g., fever, lethargy). Characteristic hemogram findings were bi- or pancytopenia with low blast numbers. Histologic examination revealed extramedullary infiltrates, especially in lymph nodes, spleen, kidney, liver, and lungs. Leukemias were classified as B-cell ( n = 3) and acute myeloid leukemia (AML) ( n = 3). Tumors in 4 cases expressed multiple lineage markers, which complicated classification. Acute leukemia should be suspected in horses with moderate-to-severe bi- or pancytopenia. Blood smears should be reviewed for neoplastic cells, and bone marrow examination is required for diagnosis. Leukemia classification is best achieved using combined morphologic, cytochemical, and immunophenotyping results. [Mh] Termos MeSH primário: Doenças dos Cavalos/patologia Leucemia de Células B/veterinária Leucemia Mieloide Aguda/veterinária [Mh] Termos MeSH secundário: Animais Biomarcadores/análise Feminino Doenças dos Cavalos/etiologia Cavalos Leucemia de Células B/etiologia Leucemia de Células B/patologia Leucemia Mieloide Aguda/etiologia Leucemia Mieloide Aguda/patologia Masculino New York [Pt] Tipo de publicação: CASE REPORTS; JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171212 [Lr] Data última revisão: 171212 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170504 [St] Status: MEDLINE [do] DOI: 10.1177/1040638717707724

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[PMID]: 28898985 [Au] Autor: Wu B; Jug R; Luedke C; Su P; Rehder C; McCall C; Lagoo AS; Wang E [Ad] Endereço: Division of Hematology, Department of Medicine, Shengjing Hospital affiliated with China Medical University, Shenyang, People's Republic of China. [Ti] Título: Lineage Switch Between B-Lymphoblastic Leukemia and Acute Myeloid Leukemia Intermediated by "Occult" Myelodysplastic Neoplasm: Two Cases of Adult Patients With Evidence of Genomic Instability and Clonal Selection by Chemotherapy. [So] Source: Am J Clin Pathol;148(2):136-147, 2017 Aug 01. [Is] ISSN: 1943-7722 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Objectives: Lineage switch occurs in rare leukemias, and the mechanism is unclear. We report two cases of B-lymphoblastic leukemia (B-ALL) relapsed as acute myeloid leukemia (AML). Methods: Retrospective review of clinical and laboratory data. Results: Complex cytogenetic abnormalities were detected in B-ALL for both cases with subclone heterogeneity. Postchemotherapy marrow biopsies showed trilineage hematopoiesis without detectable B-ALL. Cytogenetics in both showed stemline abnormalities. The cases were considered "occult" myelodysplastic syndrome (MDS) preceding B-ALL. The patients relapsed 6.5 and 9 months following induction, respectively. Case 1 relapsed as AML-M5 initially, was treated as such, and then relapsed again as B-ALL. Case 2 relapsed as AML-M6. Cytogenetics demonstrated persistent abnormalities. Both patients died soon after relapse. Conclusions: Lineage switch between B-ALL and AML could be intermediated by occult MDS. A pluripotent progenitor likely undergoes neoplastic transformation, resulting in a genomically unstable clone. This leads to a repertoire of heterogeneous subclones that may be selected by chemotherapy. Lineage switch heralds a dismal clinical outcome. [Mh] Termos MeSH primário: Leucemia de Células B/genética Leucemia de Células B/patologia Leucemia Mieloide Aguda/genética Leucemia Mieloide Aguda/patologia Segunda Neoplasia Primária/genética Segunda Neoplasia Primária/patologia [Mh] Termos MeSH secundário: Idoso Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico Transformação Celular Neoplásica/efeitos dos fármacos Transformação Celular Neoplásica/genética Aberrações Cromossômicas Instabilidade Genômica Seres Humanos Leucemia Mieloide Aguda/tratamento farmacológico Masculino Síndromes Mielodisplásicas/genética Síndromes Mielodisplásicas/patologia Adulto Jovem [Pt] Tipo de publicação: CASE REPORTS; JOURNAL ARTICLE [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171002 [Lr] Data última revisão: 171002 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170914 [St] Status: MEDLINE [do] DOI: 10.1093/ajcp/aqx055

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[PMID]: 28719798 [Au] Autor: Lichtman EI; Dotti G [Ad] Endereço: Department of Medicine, University of North Carolina, Chapel Hill, NC; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC. Electronic address: eben.lichtman@unchealth.unc.edu. [Ti] Título: Chimeric antigen receptor T-cells for B-cell malignancies. [So] Source: Transl Res;187:59-82, 2017 Sep. [Is] ISSN: 1878-1810 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The adoptive transfer of T-lymphocytes modified to express chimeric antigen receptors (CAR-Ts) has produced impressive clinical responses among patients with B-cell malignancies. This has led to a rapid expansion in the number of clinical trials over the past several years. Although CD19-specific CAR-Ts are the most extensively evaluated, CAR-Ts specific for other B-cell-associated targets have also shown promise. However, despite this success, toxicities associated with CAR-T administration remain a significant concern. There continues to be substantial heterogeneity among CAR-T products, and differences in both CAR designs and CAR-T production strategies can substantially affect clinical outcomes. Ongoing clinical studies will further elucidate these differences and many other innovative approaches are being evaluated at the preclinical level. In this review, we will discuss the background and rationale for the use of CAR-Ts, provide an overview of advances in the field, and examine the application of CAR-Ts to the treatment of B-cell malignancies, including a summary of clinical trials published to date. [Mh] Termos MeSH primário: Imunoterapia Adotiva/métodos Leucemia de Células B/terapia Linfoma de Células B/terapia Receptores de Antígenos/metabolismo Linfócitos T/fisiologia [Mh] Termos MeSH secundário: Seres Humanos Receptores de Antígenos/genética Proteínas Recombinantes de Fusão [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Receptors, Antigen); 0 (Recombinant Fusion Proteins) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170925 [Lr] Data última revisão: 170925 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170719 [St] Status: MEDLINE

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[PMID]: 28707666 [Au] Autor: Shestakova EA; Boutin M; Bourassa S; Bonneil E; Bijl JJ [Ad] Endereço: HMR Research Center, University of Montreal, Montreal, QC, Canada. [Ti] Título: [Identification of proteins associated with transcription factors HOXA9 and E2A-PBX1 by tandem affinity purification]. [So] Source: Mol Biol (Mosk);51(3):490-501, 2017 May-Jun. [Is] ISSN: 0026-8984 [Cp] País de publicação: Russia (Federation) [La] Idioma: rus [Ab] Resumo: Chimeric transcription factor E2A-PBX1 induces the development of acute lymphoblastic B-cell leukemia in children. Using a transgenic mouse model, we previously demonstrated that homeobox (HOX) gene HOXA9 genetically interact with E2A-PBX1 gene in the development of B-cell leukemia in mice. HOXA9 itself is a potent oncogene resulting in myeloid leukemia when overexpressed, which is strongly accelerated by its collaborator Meis1. HOX, PBX1 and MEIS1 proteins have been shown to form hetero dimeric or trimeric complexes in different combinations. Cooperative interaction between PBX1 and HOX proteins enhances their DNA binding specificity, essential for HOX dependent developmental programs. PBX1 is retained in E2A-PBX1, and thus the strong transcriptional activator properties of E2A-PBX1 may lead to aberrant activation of normally repressed targets of HOX-PBX complexes. However, although there is evidence that E2A-PBX1 could bind to HOX and MEIS1 proteins it is still unclear whether such complexes are actually required for leukemic transformation or whether E2A-PBX1 and HOXA9 are each part of larger protein complexes acting in independent complementing oncogenic pathways. In this study we aim to search for other HOXA9 and E2A-PBX1 interacting proteins. To identify novel proteins interacting with human E2A-PBX1 or HOXA9 we used tandem affinity purification (TAP) of protein complexes from 697 pre-B leukemic and HeLa cell lines transduced to express E2A-PBX1 or HOXA9, respectively, with covalently attached FLAG/HA peptides. The protein composition of each complex was determined using tandem mass-spectrometry. In the E2A-PBX1 containing complex we identified lymphoid transcription factor IKAROS, chromatin remodeling factors of SWI/SNF family while multiple subunits of translation initiation factor eIF3, E3 ubiquitin ligase UBR5 emerged from the HOXA9 complex as potential critical protein partners. This is the first time the protein partners of either E2A-PBX1 or HOXA9 oncoproteins were identified using an unbiased biochemical approach. The identification of translation initiation factors associated with HOXA9 might indicate a novel function for HOX proteins independent of their transcriptional activity. [Mh] Termos MeSH primário: Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética Proteínas de Ligação a DNA/genética Proteínas de Homeodomínio/genética Leucemia de Células B/genética Proteínas de Fusão Oncogênicas/genética Leucemia-Linfoma Linfoblástico de Células Precursoras/genética Proteínas Proto-Oncogênicas/genética [Mh] Termos MeSH secundário: Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo Linhagem Celular Tumoral Proteínas Cromossômicas não Histona/genética Proteínas Cromossômicas não Histona/isolamento & purificação Proteínas de Ligação a DNA/metabolismo Regulação Leucêmica da Expressão Gênica Proteínas de Homeodomínio/metabolismo Seres Humanos Fator de Transcrição Ikaros/genética Fator de Transcrição Ikaros/isolamento & purificação Leucemia de Células B/patologia Proteína 1 de Sítio de Integração Viral Ecotrópica Mielóide Proteínas de Neoplasias/genética Proteínas de Fusão Oncogênicas/metabolismo Fator de Transcrição 1 de Leucemia de Células Pré-B Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia Ligação Proteica Mapas de Interação de Proteínas Proteínas Proto-Oncogênicas/metabolismo Espectrometria de Massas em Tandem Fatores de Transcrição/genética Fatores de Transcrição/isolamento & purificação Ubiquitina-Proteína Ligases/genética Ubiquitina-Proteína Ligases/isolamento & purificação [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Chromosomal Proteins, Non-Histone); 0 (DNA-Binding Proteins); 0 (Homeodomain Proteins); 0 (IKZF1 protein, human); 0 (MEIS1 protein, human); 0 (Meis1 protein, mouse); 0 (Myeloid Ecotropic Viral Integration Site 1 Protein); 0 (Neoplasm Proteins); 0 (Oncogene Proteins, Fusion); 0 (Pre-B-Cell Leukemia Transcription Factor 1); 0 (Proto-Oncogene Proteins); 0 (SWI-SNF-B chromatin-remodeling complex); 0 (TCF3 protein, human); 0 (Transcription Factors); 0 (homeobox protein HOXA9); 0 (pbx1 protein, human); 146150-85-8 (E2A-Pbx1 fusion protein); 148971-36-2 (Ikaros Transcription Factor); EC 2.3.2.26 (UBR5 protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases) [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: 170715 [St] Status: MEDLINE [do] DOI: 10.7868/S0026898417030132

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[PMID]: 28664772 [Au] Autor: Gordon MJ; Lewis LD; Brown JR; Danilov AV [Ad] Endereço: a Department of Internal Medicine , Oregon Health & Science University , Portland , OR , USA. [Ti] Título: Bendamustine hydrochloride in patients with B-cell malignancies who have comorbidities - is there an optimal dose? [So] Source: Expert Rev Hematol;10(8):707-718, 2017 Aug. [Is] ISSN: 1747-4094 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: INTRODUCTION: The majority of patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) present with comorbidities. Many of them are poor candidates for intensive chemo-immunotherapy regimens, such as FCR (fludarabine, cyclophosphamide, rituximab). Still, most clinical trials aim to enroll 'fit' patients, who poorly represent the community oncology population. Areas covered: In the past decade, bendamustine hydrochloride, a cytotoxic agent with structural similarities to both alkylating agents and purine analogs, has received widespread use in therapy of NHL and CLL, and has demonstrated a relatively favorable toxicity profile. However, bendamustine has not been well studied in patients with hematologic malignancies who have comorbidities. Here we review the clinical data on use of bendamustine in older and unfit patients with NHL and CLL, and analyze whether there is an optimal dose of bendamustine in patients who have significant comorbidities, including renal dysfunction. Expert commentary: Reduced intensity regimens of bendamustine are effective in CLL patients with comorbidities and renal dysfunction. Even with the introduction of targeted therapies, bendamustine will likely continue to be an important therapeutic option in patients with comorbidities because of its tolerability, efficacy and cost. [Mh] Termos MeSH primário: Antineoplásicos Alquilantes/uso terapêutico Cloridrato de Bendamustina/uso terapêutico Leucemia de Células B/tratamento farmacológico Linfoma de Células B/tratamento farmacológico [Mh] Termos MeSH secundário: Antineoplásicos Alquilantes/farmacologia Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico Cloridrato de Bendamustina/farmacologia Ensaios Clínicos como Assunto Comorbidade Seres Humanos Leucemia de Células B/diagnóstico Leucemia de Células B/mortalidade Leucemia Linfocítica Crônica de Células B/diagnóstico Leucemia Linfocítica Crônica de Células B/tratamento farmacológico Leucemia Linfocítica Crônica de Células B/mortalidade Linfoma de Células B/diagnóstico Linfoma de Células B/mortalidade Linfoma não Hodgkin/diagnóstico Linfoma não Hodgkin/tratamento farmacológico Linfoma não Hodgkin/mortalidade Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antineoplastic Agents, Alkylating); 981Y8SX18M (Bendamustine Hydrochloride) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171009 [Lr] Data última revisão: 171009 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170701 [St] Status: MEDLINE [do] DOI: 10.1080/17474086.2017.1350166

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[PMID]: 28607179 [Au] Autor: Soto-Feliciano YM; Bartlebaugh JME; Liu Y; Sánchez-Rivera FJ; Bhutkar A; Weintraub AS; Buenrostro JD; Cheng CS; Regev A; Jacks TE; Young RA; Hemann MT [Ad] Endereço: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. [Ti] Título: PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes. [So] Source: Genes Dev;31(10):973-989, 2017 May 15. [Is] ISSN: 1549-5477 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Developmental and lineage plasticity have been observed in numerous malignancies and have been correlated with tumor progression and drug resistance. However, little is known about the molecular mechanisms that enable such plasticity to occur. Here, we describe the function of the plant homeodomain finger protein 6 (PHF6) in leukemia and define its role in regulating chromatin accessibility to lineage-specific transcription factors. We show that loss of in B-cell leukemia results in systematic changes in gene expression via alteration of the chromatin landscape at the transcriptional start sites of B-cell- and T-cell-specific factors. Additionally, cells show significant down-regulation of genes involved in the development and function of normal B cells, show up-regulation of genes involved in T-cell signaling, and give rise to mixed-lineage lymphoma in vivo. Engagement of divergent transcriptional programs results in phenotypic plasticity that leads to altered disease presentation in vivo, tolerance of aberrant oncogenic signaling, and differential sensitivity to frontline and targeted therapies. These findings suggest that active maintenance of a precise chromatin landscape is essential for sustaining proper leukemia cell identity and that loss of a single factor (PHF6) can cause focal changes in chromatin accessibility and nucleosome positioning that render cells susceptible to lineage transition. [Mh] Termos MeSH primário: Cromatina/genética Regulação Neoplásica da Expressão Gênica Proteínas de Homeodomínio/genética Proteínas de Homeodomínio/metabolismo Leucemia de Células B/genética Leucemia de Células B/fisiopatologia [Mh] Termos MeSH secundário: Animais Linhagem Celular Tumoral Linhagem da Célula/genética Cromatina/metabolismo Resistência a Medicamentos Antineoplásicos/genética Técnicas de Inativação de Genes Linfoma não Hodgkin/genética Camundongos Camundongos Endogâmicos C57BL Fenótipo Transdução de Sinais/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Chromatin); 0 (Homeodomain Proteins); 0 (Phf6 protein, mouse) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171115 [Lr] Data última revisão: 171115 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170614 [St] Status: MEDLINE [do] DOI: 10.1101/gad.295857.117

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[PMID]: 28575524 [Au] Autor: de Ruiter JR; Kas SM; Schut E; Adams DJ; Koudijs MJ; Wessels LFA; Jonkers J [Ad] Endereço: Division of Molecular Pathology and Cancer Genomics Netherlands, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands. [Ti] Título: Identifying transposon insertions and their effects from RNA-sequencing data. [So] Source: Nucleic Acids Res;45(12):7064-7077, 2017 Jul 07. [Is] ISSN: 1362-4962 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Insertional mutagenesis using engineered transposons is a potent forward genetic screening technique used to identify cancer genes in mouse model systems. In the analysis of these screens, transposon insertion sites are typically identified by targeted DNA-sequencing and subsequently assigned to predicted target genes using heuristics. As such, these approaches provide no direct evidence that insertions actually affect their predicted targets or how transcripts of these genes are affected. To address this, we developed IM-Fusion, an approach that identifies insertion sites from gene-transposon fusions in standard single- and paired-end RNA-sequencing data. We demonstrate IM-Fusion on two separate transposon screens of 123 mammary tumors and 20 B-cell acute lymphoblastic leukemias, respectively. We show that IM-Fusion accurately identifies transposon insertions and their true target genes. Furthermore, by combining the identified insertion sites with expression quantification, we show that we can determine the effect of a transposon insertion on its target gene(s) and prioritize insertions that have a significant effect on expression. We expect that IM-Fusion will significantly enhance the accuracy of cancer gene discovery in forward genetic screens and provide initial insight into the biological effects of insertions on candidate cancer genes. [Mh] Termos MeSH primário: Neoplasias da Mama/genética Elementos de DNA Transponíveis Leucemia de Células B/genética Mutagênese Insercional Proteínas de Neoplasias/genética Software [Mh] Termos MeSH secundário: Doença Aguda Animais Neoplasias da Mama/metabolismo Mapeamento Cromossômico/métodos Conjuntos de Dados como Assunto Modelos Animais de Doenças Feminino Sequenciamento de Nucleotídeos em Larga Escala Ensaios de Triagem em Larga Escala Seres Humanos Leucemia de Células B/metabolismo Camundongos Proteínas de Neoplasias/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (DNA Transposable Elements); 0 (Neoplasm Proteins) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171011 [Lr] Data última revisão: 171011 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170603 [St] Status: MEDLINE [do] DOI: 10.1093/nar/gkx461

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[PMID]: 28573668 [Au] Autor: Göckeritz E; Vondey V; Guastafierro A; Pizevska M; Hassenrück F; Neumann L; Hallek M; Krause G [Ad] Endereço: Department I of Internal Medicine, University Hospital of Cologne, Centre of Integrated Oncology Cologne-Bonn, CECAD Centre of Excellence on "Cellular Stress Responses in Aging-associated Diseases", University of Cologne, Cologne, Germany. [Ti] Título: Establishing a chemical genetic link between Bruton tyrosine kinase activity in malignant B cells and cell functions involved in the micro-environmental dialogue. [So] Source: Br J Haematol;178(6):949-953, 2017 Sep. [Is] ISSN: 1365-2141 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: To elucidate their mechanism of action, inhibitors of Bruton tyrosine kinase (BTK) and resistant BTK mutants were employed to dissect target-dependent cellular functions. BTK-C481S and -T474I, expressed in Ramos and NALM-6 cells, maintained BTK auto-phosphorylation under treatment with ibrutinib or dasatinib, respectively, which showed only modest cytotoxicity. Retained activity of BTK-T474 partially rescued cell migration from inhibition by dasatinib. Importantly, resistant BTK mutants reconstituted B cell receptor-triggered chemokine secretion in the presence of corresponding inhibitors, demonstrating that BTK activity is connected with cell-intrinsic functions of malignant B cells with importance for their dialogue with the micro-environment. [Mh] Termos MeSH primário: Linfócitos B/enzimologia Leucemia de Células B/genética Linfoma de Células B/genética Proteínas Tirosina Quinases/genética [Mh] Termos MeSH secundário: Antineoplásicos Quimiocinas/metabolismo Quimiotaxia/efeitos dos fármacos Dasatinibe/administração & dosagem Dasatinibe/farmacologia Relação Dose-Resposta a Droga Resistência a Medicamentos Antineoplásicos/genética Seres Humanos Leucemia de Células B/enzimologia Leucemia de Células B/patologia Linfoma de Células B/enzimologia Linfoma de Células B/patologia Mutação Fosforilação/efeitos dos fármacos Inibidores de Proteínas Quinases/farmacologia Proteínas Tirosina Quinases/antagonistas & inibidores Proteínas Tirosina Quinases/metabolismo Pirazóis/administração & dosagem Pirazóis/farmacologia Pirimidinas/administração & dosagem Pirimidinas/farmacologia Células Tumorais Cultivadas [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antineoplastic Agents); 0 (Chemokines); 0 (PCI 32765); 0 (Protein Kinase Inhibitors); 0 (Pyrazoles); 0 (Pyrimidines); EC 2.7.10.1 (Agammaglobulinaemia tyrosine kinase); EC 2.7.10.1 (Protein-Tyrosine Kinases); RBZ1571X5H (Dasatinib) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171010 [Lr] Data última revisão: 171010 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170603 [St] Status: MEDLINE [do] DOI: 10.1111/bjh.14781

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[PMID]: 28481918 [Au] Autor: Gutierrez-Camino A; Martin-Guerrero I; Garcia de Andoin N; Sastre A; Carbone Bañeres A; Astigarraga I; Navajas A; Garcia-Orad A [Ad] Endereço: Department of Genetics, Physic Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, Leioa, Spain. [Ti] Título: Confirmation of involvement of new variants at CDKN2A/B in pediatric acute lymphoblastic leukemia susceptibility in the Spanish population. [So] Source: PLoS One;12(5):e0177421, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The locus CDKN2A/B (9p21.3), which comprises the tumor suppressors genes CDKN2A and CDKN2B and the long noncoding RNA (lncRNA) known as ANRIL (or CDKN2B-AS), was associated with childhood acute lymphoblastic leukemia (ALL) susceptibility in several genome wide association studies (GWAS). However, the variants associated in the diverse studies were different. Recently, new and independent SNPs deregulating the locus function were also identified in association with ALL risk. This diversity in the results may be explained because different variants in each population could alter CDKN2A/B locus function through diverse mechanisms. Therefore, the aim of this study was to determine whether the annotated risk variants in the CDKN2A/B locus affect the susceptibility of B cell precursor ALL (B-ALL) in our Spanish population and explore if other SNPs altering additional regulatory mechanisms could be also involved. We analyzed the four SNPs proposed by GWAs and two additional SNPs in miRNA binding sites in 217 pediatric patients with B-ALL and 330 healthy controls. The SNPs rs2811712, rs3731249, rs3217992 and rs2811709 were associated with B-ALL susceptibility in our Spanish population. ALL subtypes analyses showed that rs2811712 was associated with B-hyperdiploid ALL. These results provide evidence for the influence of genetic variants at CDKN2A/B locus with the risk of developing B-ALL. [Mh] Termos MeSH primário: Inibidor de Quinase Dependente de Ciclina p15/genética Inibidor de Quinase Dependente de Ciclina p18/genética Leucemia de Células B/genética Mutação Leucemia-Linfoma Linfoblástico de Células Precursoras/genética [Mh] Termos MeSH secundário: Adolescente Criança Pré-Escolar Feminino Genótipo Seres Humanos Lactente Masculino Espanha [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (CDKN2A protein, human); 0 (CDKN2B protein, human); 0 (Cyclin-Dependent Kinase Inhibitor p15); 0 (Cyclin-Dependent Kinase Inhibitor p18) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170915 [Lr] Data última revisão: 170915 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170509 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0177421

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