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  • 1
    Language: English
    In: Cell death & disease, 2013-02-21, Vol.4 (2), p.e500-e500
    Description: One of the biggest challenges in tumour research is the possibility to reprogram cancer cells towards less aggressive phenotypes. In this study, we reprogrammed primary Glioblastoma multiforme (GBM)-derived cells towards a more differentiated and less oncogenic phenotype by activating the Wnt pathway in a hypoxic microenvironment. Hypoxia usually correlates with malignant behaviours in cancer cells, but it has been recently involved, together with Wnt signalling, in the differentiation of embryonic and neural stem cells. Here, we demonstrate that treatment with Wnt ligands, or overexpression of β-catenin, mediate neuronal differentiation and halt proliferation in primary GBM cells. An hypoxic environment cooperates with Wnt-induced differentiation, in line with our finding that hypoxia inducible factor-1α (HIF-1α) is instrumental and required to sustain the expression of β-catenin transcriptional partners TCF-1 and LEF-1. In addition, we also found that Wnt-induced GBM cell differentiation inhibits Notch signalling, and thus gain of Wnt and loss of Notch cooperate in the activation of a pro-neuronal differentiation program. Intriguingly, the GBM sub-population enriched of cancer stem cells (CD133(+) fraction) is the primary target of the pro-differentiating effects mediated by the crosstalk between HIF-1α, Wnt, and Notch signalling. By using zebrafish transgenics and mutants as model systems to visualize and manipulate in vivo the Wnt pathway, we confirm that Wnt pathway activation is able to promote neuronal differentiation and inhibit Notch signalling of primary human GBM cells also in this in vivo set-up. In conclusion, these findings shed light on an unsuspected crosstalk between hypoxia, Wnt and Notch signalling in GBM, and suggest the potential to manipulate these microenvironmental signals to blunt GBM malignancy.
    Subject(s): Neoplastic Stem Cells - cytology ; Receptors, Notch - metabolism ; Humans ; Lymphoid Enhancer-Binding Factor 1 - genetics ; Tumor Microenvironment ; Transplantation, Heterologous ; Gene Expression Profiling ; Wnt Proteins - metabolism ; Neurogenesis ; Cell Hypoxia ; Neoplastic Stem Cells - metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Glioblastoma - metabolism ; Transcription, Genetic ; Larva - genetics ; Tumor Cells, Cultured ; T Cell Transcription Factor 1 - metabolism ; Wnt Signaling Pathway ; Larva - metabolism ; Survival Rate ; Animals, Genetically Modified - metabolism ; Lymphoid Enhancer-Binding Factor 1 - metabolism ; Zebrafish - growth & development ; beta Catenin - metabolism ; beta Catenin - genetics ; T Cell Transcription Factor 1 - genetics ; Animals ; Glioblastoma - pathology ; Glioblastoma - mortality ; Hypoxia ; Wnt ; Original ; glioblastoma stem cells ; Notch
    ISSN: 2041-4889
    E-ISSN: 2041-4889
    Source: Nature Open Access
    Source: PubMed Central
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  • 2
    Language: English
    In: Leukemia, 2011, Vol.25 (12), p.1840-1848
    Description: Massively parallel pyrosequencing allows sensitive deep sequencing to detect molecular aberrations. Thus far, data are limited on the technical performance in a clinical diagnostic setting. Here, we investigated as an international consortium the robustness, precision and reproducibility of amplicon next-generation deep sequencing across 10 laboratories in eight countries. In a cohort of 18 chronic myelomonocytic leukemia patients, mutational analyses were performed on TET2, a frequently mutated gene in myeloproliferative neoplasms. Additionally, hotspot regions of CBL and KRAS were investigated. The study was executed using GS FLX sequencing instruments and the small volume 454 Life Sciences Titanium emulsion PCR setup. We report a high concordance in mutation detection across all laboratories, including a robust detection of novel variants, which were undetected by standard Sanger sequencing. The sensitivity to detect low-level variants present with as low as 1-2% frequency, compared with the 20% threshold for Sanger-based sequencing is increased. Together with the output of high-quality long reads and fast run time, we demonstrate the utility of deep sequencing in clinical applications. In conclusion, this multicenter analysis demonstrated that amplicon-based deep sequencing is technically feasible, achieves high concordance across multiple laboratories and allows a broad and in-depth molecular characterization of cancer specimens with high diagnostic sensitivity.
    Subject(s): Hematologic and hematopoietic diseases ; Biological and medical sciences ; Medical sciences ; Proto-Oncogene Proteins c-cbl - genetics ; ras Proteins - genetics ; Proto-Oncogene Proteins p21(ras) ; Prognosis ; Humans ; Leukemia, Myelomonocytic, Chronic - genetics ; Middle Aged ; Male ; Proto-Oncogene Proteins - genetics ; DNA-Binding Proteins - genetics ; Mutation - genetics ; DNA Mutational Analysis ; Polymerase Chain Reaction ; Aged, 80 and over ; Female ; Aged ; High-Throughput Nucleotide Sequencing ; Cohort Studies ; Nucleotide sequence ; Gene mutations ; Physiological aspects ; Genetic aspects ; Research ; Diagnosis ; Myeloproliferative disorders
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 3
    Language: English
    In: Leukemia, 2017-04, Vol.31 (4), p.1007-1011
    Subject(s): Phosphorylation - physiology ; TOR Serine-Threonine Kinases - metabolism ; Humans ; Cells, Cultured ; Hematopoietic Stem Cells - metabolism ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism ; Precursor Cells, T-Lymphoid - metabolism ; Myeloid Cells - metabolism ; Transcriptome - physiology ; Proteome - metabolism ; Calcineurin - metabolism ; STAT3 Transcription Factor - metabolism
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: Leukemia, 2016-09-01, Vol.30 (9), p.1887
    Description: cAMP response element binding protein (CREB) is frequently overexpressed in acute myeloid leukemia (AML) and acts as a proto-oncogene; however, it is still debated whether such overactivation alone is able to induce leukemia as its pathogenetic downstream signaling is still unclear. We generated a zebrafish model overexpressing CREB in the myeloid lineage, which showed an aberrant regulation of primitive hematopoiesis, and in 79% of adult CREB-zebrafish a block of myeloid differentiation, triggering to a monocytic leukemia akin the human counterpart. Gene expression analysis of CREB-zebrafish revealed a signature of 20 differentially expressed human homologous CREB targets in common with pediatric AML. Among them, we demonstrated that CREB overexpression increased CCAAT-enhancer-binding protein-[delta] (C/EBP[delta]) levels to cause myeloid differentiation arrest, and the silencing of CREB-C/EBP[delta] axis restored myeloid terminal differentiation. Then, C/EBP[delta] overexpression was found to identify a subset of pediatric AML affected by a block of myeloid differentiation at monocytic stage who presented a significant higher relapse risk and the enrichment of aggressive signatures. Finally, this study unveils the aberrant activation of CREB-C/EBP[delta] axis concurring to AML onset by disrupting the myeloid cell differentiation process. We provide a novel in vivo model to perform high-throughput drug screening for AML cure improvement.
    Subject(s): Pediatrics ; Analysis ; Cyclic adenylic acid ; Genetic aspects ; Gene expression ; Cell differentiation ; Protein binding
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
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  • 5
    Language: English
    In: Leukemia, 2017-02, Vol.31 (2), p.498-501
    Subject(s): Lymphoma, Large-Cell, Anaplastic - classification ; Protein-Tyrosine Kinases - metabolism ; Child ; Humans ; Lymphoma, Large-Cell, Anaplastic - metabolism
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
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  • 6
    Language: English
    In: Plant physiology (Bethesda), 2008-04-01, Vol.146 (4), p.1878-1891
    Description: Protein-protein interactions among enzymes of amylopectin biosynthesis were investigated in developing wheat (Triticum aestivum) endosperm. Physical interactions between starch branching enzymes (SBEs) and starch synthases (SSs) were identified from endosperm amyloplasts during the active phase of starch deposition in the developing grain using immunoprecipitation and cross-linking strategies. Coimmunoprecipitation experiments using peptide-specific antibodies indicate that at least two distinct complexes exist containing SSI, SSIIa, and either of SBEIIa or SBEIIb. Chemical cross linking was used to identify protein complexes containing SBEs and SSs from amyloplast extracts. Separation of extracts by gel filtration chromatography demonstrated the presence of SBE and SS forms in protein complexes of around 260 kD and that SBEII forms may also exist as homodimers. Analysis of cross-linked 260-kD aggregation products from amyloplast lysates by mass spectrometry confirmed SSI, SSIIa, and SBEII forms as components of one or more protein complexes in amyloplasts. In vitro phosphorylation experiments with y-³²P-ATP indicated that SSII and both forms of SBEII are phosphorylated. Treatment of the partially purified 260-kD SS-SBE complexes with alkaline phosphatase caused dissociation of the assembly into the respective monomeric proteins, indicating that formation of SS-SBE complexes is phosphorylation dependent. The 260-kD SS-SBEII protein complexes are formed around 10 to 15 d after pollination and were shown to be catalytically active with respect to both SS and SBE activities. Prior to this developmental stage, SSI, SSII, and SBEII forms were detectable only in monomeric form. High molecular weight forms of SBEII demonstrated a higher affinity for in vitro glucan substrates than monomers. These results provide direct evidence for the existence of protein complexes involved in amylopectin biosynthesis.
    Subject(s): Protein isoforms ; Enzymes ; Antiserum ; Biochemical Processes and Macromolecular Structures ; Gels ; Glucans ; Antibodies ; Starches ; Endosperm ; Amyloplasts ; Plastids ; Fundamental and applied biological sciences. Psychology ; Biological and medical sciences ; Metabolism ; Plant physiology and development ; Amino Acid Sequence ; Phosphorylation ; Immunoprecipitation ; Starch - biosynthesis ; Electrophoresis, Polyacrylamide Gel ; Molecular Sequence Data ; Triticum - metabolism ; Mass Spectrometry ; Glucans - metabolism ; Plant Proteins - metabolism ; Triticum - enzymology ; Chromatography, Gel ; Enzymes - metabolism ; Viral antibodies ; Chemical properties ; Wheat ; Chromatography
    ISSN: 0032-0889
    E-ISSN: 1532-2548
    Source: American Society of Plant Biologists
    Source: JSTOR Life Sciences
    Source: HighWire Press (Free Journals)
    Source: Hellenic Academic Libraries Link
    Source: JSTOR Ecology & Botany II
    Source: PubMed Central
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  • 7
    Language: English
    In: Leukemia, 2015-10, Vol.29 (10), p.2107-2110
    Subject(s): Prognosis ; Humans ; Mutation - genetics ; Sequence Analysis, DNA ; Ikaros Transcription Factor - genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics ; Gene Deletion ; Polymorphism, Single Nucleotide - genetics ; Biomarkers, Tumor - genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Child ; Philadelphia Chromosome ; Cohort Studies ; Transcription factors ; Human chromosome abnormalities ; Development and progression ; Genetic aspects ; Acute lymphocytic leukemia ; Properties ; Gene expression ; Health aspects
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    In: Leukemia, 2012, Vol.26 (7), p.1717-1719
    Subject(s): Hematologic and hematopoietic diseases ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Biological and medical sciences ; Medical sciences ; Prognosis ; Oligonucleotide Array Sequence Analysis ; Humans ; Risk Factors ; Child, Preschool ; Infant ; Male ; Gene Expression Profiling ; Leukemia, Myeloid, Acute - etiology ; Myelodysplastic Syndromes - complications ; Algorithms ; Leukemia, Myeloid, Acute - diagnosis ; Cell Transformation, Neoplastic - genetics ; Adolescent ; Female ; Biomarkers, Tumor - genetics ; Myelodysplastic Syndromes - genetics ; Cell Transformation, Neoplastic - pathology ; Child ; Complications and side effects ; Care and treatment ; Research ; Gene expression ; Leukemia in children ; Myelodysplastic syndromes
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 9
    Language: English
    In: Leukemia, 2011, Vol.25 (3), p.560-563
    Subject(s): Hematologic and hematopoietic diseases ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Biological and medical sciences ; Medical sciences ; Translocation, Genetic ; Histone-Lysine N-Methyltransferase ; Genomics ; Humans ; Male ; Gene Expression Profiling ; Chromosomes, Human, Pair 6 ; Myosins - genetics ; Myeloid-Lymphoid Leukemia Protein - genetics ; Kinesin - genetics ; Female ; Chromosomes, Human, Pair 11 ; Child ; Leukemia, Myeloid, Acute - genetics ; Gene expression ; Research
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Academic Search Ultimate
    Source: Alma/SFX Local Collection
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  • 10
    Language: English
    In: Blood cancer journal (New York), 2013-11-15, Vol.3 (11), p.e160-e160
    Description: To diagnose juvenile myelomonocytic leukemia (JMML) is sometimes challenging, because around 10% of patients lack molecular abnormalities affecting Ras-MAPK (mitogen-activated protein kinase) pathway and other diseases such as cytomegalovirus infection can mimic clinical signs of JMML. In order to validate a phospho-specific flow cytometry assay assessing phospho-signal transducer and activator of transcription factor 5 (p-STAT5) as a new diagnostic tool for JMML, we examined 22 samples from children with JMML and 47 controls. CD33+/CD34+ cells from 22 patients with JMML showed hyperphosphorylation of STAT5 induced by sub-saturating doses of granulocyte-macrophage colony-stimulating factor (GM-CSF). Using a training set of samples (11 JMML and 23 controls), we identified a threshold for p-STAT5-positive after stimulation with 0.1 ng/ml GM-CSF (17.17%) that discriminates JMML from controls. This threshold was validated in an independent series (11 JMML, 24 controls and 7 cases with diseases other than JMML) where we demonstrated that patients with JMML could be distinguished from other subjects with a sensitivity of 91% (confidence interval (CI) 59-100%) and a specificity of 87% (CI 70-96%). Positive and negative predictive values were 71% (CI 42-92%) and 96% (CI 82-100%), respectively. In conclusion, flow cytometric p-STAT5 profiling is a reliable diagnostic tool for identifying patients with JMML and can contribute to consistency of current diagnostic criteria.
    Subject(s): juvenile myelomonocytic leukemia ; phospho-STAT5 ; phospho-specific flow cytometry ; GM-CSF ; Original
    ISSN: 2044-5385
    E-ISSN: 2044-5385
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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