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  1. Article ; Online: Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth.

    Kellaway, Sophie G / Potluri, Sandeep / Keane, Peter / Blair, Helen J / Ames, Luke / Worker, Alice / Chin, Paulynn S / Ptasinska, Anetta / Derevyanko, Polina K / Adamo, Assunta / Coleman, Daniel J L / Khan, Naeem / Assi, Salam A / Krippner-Heidenreich, Anja / Raghavan, Manoj / Cockerill, Peter N / Heidenreich, Olaf / Bonifer, Constanze

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 1359

    Abstract: Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell ... ...

    Abstract Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.
    MeSH term(s) Humans ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Mutation ; Stem Cells/metabolism ; Neoplastic Stem Cells/metabolism
    Language English
    Publishing date 2024-02-14
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-45691-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Identification and interrogation of the gene regulatory network of CEBPA-double mutant acute myeloid leukemia.

    Adamo, Assunta / Chin, Paulynn / Keane, Peter / Assi, Salam A / Potluri, Sandeep / Kellaway, Sophie G / Coleman, Daniel / Ames, Luke / Ptasinska, Anetta / Delwel, H Ruud / Cockerill, Peter N / Bonifer, Constanze

    Leukemia

    2022  Volume 37, Issue 1, Page(s) 102–112

    Abstract: Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy caused by mutations in genes encoding transcriptional and epigenetic regulators together with signaling genes. It is characterized by a disturbance of differentiation and abnormal ... ...

    Abstract Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy caused by mutations in genes encoding transcriptional and epigenetic regulators together with signaling genes. It is characterized by a disturbance of differentiation and abnormal proliferation of hematopoietic progenitors. We have previously shown that each AML subtype establishes its own core gene regulatory network (GRN), consisting of transcription factors binding to their target genes and imposing a specific gene expression pattern that is required for AML maintenance. In this study, we integrate gene expression, open chromatin and ChIP data with promoter-capture Hi-C data to define a refined core GRN common to all patients with CEBPA-double mutant (CEBPA
    MeSH term(s) Humans ; Gene Regulatory Networks ; CCAAT-Enhancer-Binding Proteins/genetics ; CCAAT-Enhancer-Binding Proteins/metabolism ; CCAAT-Enhancer-Binding Protein-alpha/genetics ; CCAAT-Enhancer-Binding Protein-alpha/metabolism ; Mutation ; Cell Differentiation/genetics ; Leukemia, Myeloid, Acute/pathology
    Chemical Substances CCAAT-Enhancer-Binding Proteins ; CCAAT-Enhancer-Binding Protein-alpha ; CEBPA protein, human
    Language English
    Publishing date 2022-11-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 807030-1
    ISSN 1476-5551 ; 0887-6924
    ISSN (online) 1476-5551
    ISSN 0887-6924
    DOI 10.1038/s41375-022-01744-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2295: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer.

    Donnarumma, Elvira / Fiore, Danilo / Nappa, Martina / Roscigno, Giuseppina / Adamo, Assunta / Iaboni, Margherita / Russo, Valentina / Affinito, Alessandra / Puoti, Ilaria / Quintavalle, Cristina / Rienzo, Anna / Piscuoglio, Salvatore / Thomas, Renato / Condorelli, Gerolama

    Oncotarget

    2017  Volume 8, Issue 12, Page(s) 19592–19608

    Abstract: Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment. They may drive tumor progression, although the mechanisms involved are still poorly understood. Exosomes have emerged as important mediators of intercellular ... ...

    Abstract Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment. They may drive tumor progression, although the mechanisms involved are still poorly understood. Exosomes have emerged as important mediators of intercellular communication in cancer. They mediate horizontal transfer of microRNAs (miRs), mRNAs and proteins, thus affecting breast cancer progression. Differential expression profile analysis identified three miRs (miRs -21, -378e, and -143) increased in exosomes from CAFs as compared from normal fibroblasts. Immunofluorescence indicated that exosomes may be transferred from CAFs to breast cancer cells, releasing their cargo miRs. Breast cancer cells (BT549, MDA-MB-231, and T47D lines) exposed to CAF exosomes or transfected with those miRs exhibited a significant increased capacity to form mammospheres, increased stem cell and epithelial-mesenchymal transition (EMT) markers, and anchorage-independent cell growth. These effects were reverted by transfection with anti-miRs. Similarly to CAF exosomes, normal fibroblast exosomes transfected with miRs -21, -378e, and -143 promoted the stemness and EMT phenotype of breast cancer cells. Thus, we provided evidence for the first time of the role of CAF exosomes and their miRs in the induction of the stemness and EMT phenotype in different breast cancer cell lines. Indeed, CAFs strongly promote the development of an aggressive breast cancer cell phenotype.
    MeSH term(s) Apoptosis ; Biomarkers, Tumor/genetics ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cancer-Associated Fibroblasts ; Cell Proliferation ; Epithelial-Mesenchymal Transition ; Exosomes/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; MicroRNAs/genetics ; Neoplasm Staging ; Phenotype ; Prognosis ; Signal Transduction ; Tumor Cells, Cultured ; Tumor Microenvironment/genetics
    Chemical Substances Biomarkers, Tumor ; MIRN143 microRNA, human ; MIRN21 microRNA, human ; MIRN378 microRNA, human ; MicroRNAs
    Language English
    Publishing date 2017-03-21
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.14752
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: MiR-24 induces chemotherapy resistance and hypoxic advantage in breast cancer.

    Roscigno, Giuseppina / Puoti, Ilaria / Giordano, Immacolata / Donnarumma, Elvira / Russo, Valentina / Affinito, Alessandra / Adamo, Assunta / Quintavalle, Cristina / Todaro, Matilde / Vivanco, Maria dM / Condorelli, Gerolama

    Oncotarget

    2017  Volume 8, Issue 12, Page(s) 19507–19521

    Abstract: Breast cancer remains one of the leading causes of cancer mortality among women. It has been proved that the onset of cancer depends on a very small pool of tumor cells with a phenotype similar to that of normal adult stem cells. Cancer stem cells (CSC) ... ...

    Abstract Breast cancer remains one of the leading causes of cancer mortality among women. It has been proved that the onset of cancer depends on a very small pool of tumor cells with a phenotype similar to that of normal adult stem cells. Cancer stem cells (CSC) possess self-renewal and multilineage differentiation potential as well as a robust ability to sustain tumorigenesis. Evidence suggests that CSCs contribute to chemotherapy resistance and to survival under hypoxic conditions. Interestingly, hypoxia in turn regulates self-renewal in CSCs and these effects may be primarily mediated by hypoxic inducible factors (HIFs). Recently, microRNAs (miRNAs) have emerged as critical players in the maintenance of pluripotency and self-renewal in normal and cancer stem cells. Here, we demonstrate that miR-24 is upregulated in breast CSCs and that its overexpression increases the number of mammospheres and the expression of stem cell markers. MiR-24 also induces apoptosis resistance through the regulation of BimL expression. Moreover, we identify a new miR-24 target, FIH1, which promotes HIFα degradation: miR-24 increases under hypoxic conditions, causing downregulation of FIH1 and upregulation of HIF1α. In conclusion, miR-24 hampers chemotherapy-induced apoptosis in breast CSCs and increases cell resistance to hypoxic conditions through an FIH1-HIFα pathway.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Hypoxia/genetics ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Self Renewal/genetics ; Cisplatin/pharmacology ; Drug Resistance, Neoplasm/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; MicroRNAs/genetics ; Mixed Function Oxygenases/genetics ; Mixed Function Oxygenases/metabolism ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Tumor Cells, Cultured
    Chemical Substances Antineoplastic Agents ; Biomarkers, Tumor ; HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; MIRN24 microRNA, human ; MicroRNAs ; Repressor Proteins ; Mixed Function Oxygenases (EC 1.-) ; HIF1AN protein, human (EC 1.14.11.-) ; Cisplatin (Q20Q21Q62J)
    Language English
    Publishing date 2017-03-21
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.14470
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: miR-340 predicts glioblastoma survival and modulates key cancer hallmarks through down-regulation of NRAS.

    Fiore, Danilo / Donnarumma, Elvira / Roscigno, Giuseppina / Iaboni, Margherita / Russo, Valentina / Affinito, Alessandra / Adamo, Assunta / De Martino, Fabio / Quintavalle, Cristina / Romano, Giulia / Greco, Adelaide / Soini, Ylermi / Brunetti, Arturo / Croce, Carlo M / Condorelli, Gerolama

    Oncotarget

    2016  Volume 7, Issue 15, Page(s) 19531–19547

    Abstract: Glioblastoma is the most common primary brain tumor in adults; with a survival rate of 12 months from diagnosis. However, a small subgroup of patients, termed long-term survivors (LTS), has a survival rate longer then 12-14 months. There is thus ... ...

    Abstract Glioblastoma is the most common primary brain tumor in adults; with a survival rate of 12 months from diagnosis. However, a small subgroup of patients, termed long-term survivors (LTS), has a survival rate longer then 12-14 months. There is thus increasing interest in the identification of molecular signatures predicting glioblastoma prognosis and in how to improve the therapeutic approach. Here, we report miR-340 as prognostic tumor-suppressor microRNA for glioblastoma. We analyzed microRNA expression in > 500 glioblastoma patients and found that although miR-340 is strongly down-regulated in glioblastoma overall, it is up-regulated in LTS patients compared to short-term survivors (STS). Indeed, miR-340 expression predicted better prognosis in glioblastoma patients. Coherently, overexpression of miR-340 in glioblastoma cells was found to produce a tumor-suppressive activity. We identified NRAS mRNA as a critical, direct target of miR-340: in fact, miR-340 negatively influenced multiple aspects of glioblastoma tumorigenesis by down-regulating NRAS and downstream AKT and ERK pathways. Thus, we demonstrate that expression of miR-340 in glioblastoma is responsible for a strong tumor-suppressive effect in LTS patients by down-regulating NRAS. miR-340 may thus represent a novel marker for glioblastoma diagnosis and prognosis, and may be developed into a tool to improve treatment of glioblastoma.
    Language English
    Publishing date 2016-04-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.6968
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: RYK promotes the stemness of glioblastoma cells via the WNT/ β-catenin pathway.

    Adamo, Assunta / Fiore, Danilo / De Martino, Fabio / Roscigno, Giuseppina / Affinito, Alessandra / Donnarumma, Elvira / Puoti, Ilaria / Ricci-Vitiani, Lucia / Pallini, Roberto / Quintavalle, Cristina / Condorelli, Gerolama

    Oncotarget

    2017  

    Abstract: Glioblastoma multiforme (GBM) is characterized by a strong self-renewal potential and a poor differentiation state. Since receptor-like tyrosine kinase (RYK) activates the WNT/β-catenin pathway essential for cancer stem cell maintenance, we evaluated its ...

    Abstract Glioblastoma multiforme (GBM) is characterized by a strong self-renewal potential and a poor differentiation state. Since receptor-like tyrosine kinase (RYK) activates the WNT/β-catenin pathway essential for cancer stem cell maintenance, we evaluated its contribution in conferring stemness to GBM cells. Here, we report that Ryk (related-to-receptor tyrosine kinase), an atypical tyrosine kinase receptor, is upregulated in samples from GBM patients as well as in GSCs. Ryk overexpression confers stemness properties to GBM cells through the modulation of the canonical Wnt signaling and by promoting the activation of pluripotency-related transcription factor circuitry and neurosphere formation ability. In contrast, siRNA-mediated knockdown of Ryk expression suppresses this stem-like phenotype. Rescue experiments reveal that stemness-promoting activity of Ryk is attributable, at least in part, to β-catenin stabilization. Furthermore, Ryk overexpression improves cell motility and anchorage independent cell growth. Taken together, our findings demonstrate that Ryk promotes stem cell-like and tumorigenic features to glioma cells its essential for the maintenance of GSCs and could be a target of novel therapies.
    Language English
    Publishing date 2017-01-09
    Publishing country United States
    Document type Journal Article
    ISSN 1949-2553
    ISSN (online) 1949-2553
    DOI 10.18632/oncotarget.14564
    Database MEDical Literature Analysis and Retrieval System OnLINE

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