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  1. Artikel: Metabolic Reprogramming and Cell Adhesion in Acute Leukemia Adaptation to the CNS Niche.

    Sharma, Nitesh D / Keewan, Esra'a / Matlawska-Wasowska, Ksenia

    Frontiers in cell and developmental biology

    2021  Band 9, Seite(n) 767510

    Abstract: Involvement of the Central Nervous System (CNS) in acute leukemia confers poor prognosis and lower overall survival. Existing CNS-directed therapies are associated with a significant risk of short- or long-term toxicities. Leukemic cells can ... ...

    Abstract Involvement of the Central Nervous System (CNS) in acute leukemia confers poor prognosis and lower overall survival. Existing CNS-directed therapies are associated with a significant risk of short- or long-term toxicities. Leukemic cells can metabolically adapt and survive in the microenvironment of the CNS. The supporting role of the CNS microenvironment in leukemia progression and dissemination has not received sufficient attention. Understanding the mechanism by which leukemic cells survive in the nutrient-poor and oxygen-deprived CNS microenvironment will lead to the development of more specific and less toxic therapies. Here, we review the current literature regarding the roles of metabolic reprogramming in leukemic cell adhesion and survival in the CNS.
    Sprache Englisch
    Erscheinungsdatum 2021-12-10
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2021.767510
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Epigenetic silencing of SOCS5 potentiates JAK-STAT signaling and progression of T-cell acute lymphoblastic leukemia.

    Sharma, Nitesh D / Nickl, Christian K / Kang, Huining / Ornatowski, Wojciech / Brown, Roger / Ness, Scott A / Loh, Mignon L / Mullighan, Charles G / Winter, Stuart S / Hunger, Stephen P / Cannon, Judy L / Matlawska-Wasowska, Ksenia

    Cancer science

    2019  Band 110, Heft 6, Seite(n) 1931–1946

    Abstract: Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely ... ...

    Abstract Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.
    Mesh-Begriff(e) Animals ; Cell Line ; Cell Line, Tumor ; DNA (Cytosine-5-)-Methyltransferases/genetics ; DNA (Cytosine-5-)-Methyltransferases/metabolism ; DNA Methyltransferase 3A ; Disease Progression ; Epigenesis, Genetic ; Gene Expression Profiling ; Humans ; Janus Kinases/genetics ; Janus Kinases/metabolism ; Jurkat Cells ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; RNAi Therapeutics/methods ; Receptors, Cytokine/genetics ; Receptors, Cytokine/metabolism ; STAT Transcription Factors/genetics ; STAT Transcription Factors/metabolism ; Signal Transduction/genetics ; Suppressor of Cytokine Signaling Proteins/genetics ; Suppressor of Cytokine Signaling Proteins/metabolism ; Survival Analysis ; Xenograft Model Antitumor Assays/methods
    Chemische Substanzen DNMT3A protein, human ; Dnmt3a protein, mouse ; Receptors, Cytokine ; SOCS5 protein, human ; STAT Transcription Factors ; Suppressor of Cytokine Signaling Proteins ; DNA (Cytosine-5-)-Methyltransferases (EC 2.1.1.37) ; DNA Methyltransferase 3A (EC 2.1.1.37) ; Janus Kinases (EC 2.7.10.2)
    Sprache Englisch
    Erscheinungsdatum 2019-05-03
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2115647-5
    ISSN 1349-7006 ; 1349-7006
    ISSN (online) 1349-7006
    ISSN 1349-7006
    DOI 10.1111/cas.14021
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel: Dysregulated transcriptional networks in

    Kang, Huining / Sharma, Nitesh D / Nickl, Christian K / Devidas, Meenakshi / Loh, Mignon L / Hunger, Stephen P / Dunsmore, Kimberly P / Winter, Stuart S / Matlawska-Wasowska, Ksenia

    Biomarker research

    2018  Band 6, Seite(n) 27

    Abstract: For children and young adults with T-lineage acute lymphoblastic leukemia (T-ALL), event free survival following relapse is < 10%. We recently showed that rearrangements of the mixed lineage leukemia gene ( ...

    Abstract For children and young adults with T-lineage acute lymphoblastic leukemia (T-ALL), event free survival following relapse is < 10%. We recently showed that rearrangements of the mixed lineage leukemia gene (
    Sprache Englisch
    Erscheinungsdatum 2018-08-23
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2699926-2
    ISSN 2050-7771
    ISSN 2050-7771
    DOI 10.1186/s40364-018-0141-z
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: High-Throughput Flow Cytometry Identifies Small-Molecule Inhibitors for Drug Repurposing in T-ALL.

    Perez, Dominique R / Nickl, Christian K / Waller, Anna / Delgado-Martin, Cristina / Woods, Travis / Sharma, Nitesh D / Hermiston, Michelle L / Loh, Mignon L / Hunger, Stephen P / Winter, Stuart S / Chigaev, Alexandre / Edwards, Bruce / Sklar, Larry A / Matlawska-Wasowska, Ksenia

    SLAS discovery : advancing life sciences R & D

    2018  Band 23, Heft 7, Seite(n) 732–741

    Abstract: Kinase inhibitors have dramatically increased patient survival in a multitude of cancers, including hematological malignancies. However, kinase inhibitors have not yet been integrated into current clinical trials for patients with T-cell-lineage acute ... ...

    Abstract Kinase inhibitors have dramatically increased patient survival in a multitude of cancers, including hematological malignancies. However, kinase inhibitors have not yet been integrated into current clinical trials for patients with T-cell-lineage acute lymphoblastic leukemia (T-ALL). In this study, we used a high-throughput flow cytometry (HTFC) approach to test a collection of small-molecule inhibitors, including 26 FDA-approved tyrosine kinase inhibitors in a panel of T-ALL cell lines and patient-derived xenografts. Because hypoxia is known to cause resistance to chemotherapy, we developed a synthetic niche that mimics the low oxygen levels found in leukemic bone marrow to evaluate the effects of hypoxia on the tested inhibitors. Drug sensitivity screening was performed using the Agilent BioCel automated liquid handling system integrated with the HyperCyt HT flow cytometry platform, and the uptake of propidium iodide was used as an indication of cell viability. The HTFC dose-response testing identified several compounds that were efficacious in both normal and hypoxic conditions. This study shows that some clinically approved kinase inhibitors target T-ALL in the hypoxic niche of the bone marrow.
    Mesh-Begriff(e) Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Drug Discovery/methods ; Drug Repositioning/methods ; Flow Cytometry/methods ; High-Throughput Screening Assays ; Humans ; Mice ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Small Molecule Libraries
    Chemische Substanzen Antineoplastic Agents ; Protein Kinase Inhibitors ; Small Molecule Libraries
    Sprache Englisch
    Erscheinungsdatum 2018-05-10
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2885123-7
    ISSN 2472-5560 ; 2472-5552
    ISSN (online) 2472-5560
    ISSN 2472-5552
    DOI 10.1177/2472555218774248
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Verfügbar in ZB MED Köln/Königswinter

    Zs.A 4911: Hefte anzeigen Standort:
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  5. Artikel ; Online: RUNX2 regulates leukemic cell metabolism and chemotaxis in high-risk T cell acute lymphoblastic leukemia.

    Matthijssens, Filip / Sharma, Nitesh D / Nysus, Monique / Nickl, Christian K / Kang, Huining / Perez, Dominique R / Lintermans, Beatrice / Van Loocke, Wouter / Roels, Juliette / Peirs, Sofie / Demoen, Lisa / Pieters, Tim / Reunes, Lindy / Lammens, Tim / De Moerloose, Barbara / Van Nieuwerburgh, Filip / Deforce, Dieter L / Cheung, Laurence C / Kotecha, Rishi S /
    Risseeuw, Martijn Dp / Van Calenbergh, Serge / Takarada, Takeshi / Yoneda, Yukio / van Delft, Frederik W / Lock, Richard B / Merkley, Seth D / Chigaev, Alexandre / Sklar, Larry A / Mullighan, Charles G / Loh, Mignon L / Winter, Stuart S / Hunger, Stephen P / Goossens, Steven / Castillo, Eliseo F / Ornatowski, Wojciech / Van Vlierberghe, Pieter / Matlawska-Wasowska, Ksenia

    The Journal of clinical investigation

    2021  Band 131, Heft 6

    Abstract: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show that Runt-related transcription factor 2 (RUNX2) was upregulated in high-risk T-ALL with KMT2A ... ...

    Abstract T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with inferior outcome compared with that of B cell ALL. Here, we show that Runt-related transcription factor 2 (RUNX2) was upregulated in high-risk T-ALL with KMT2A rearrangements (KMT2A-R) or an immature immunophenotype. In KMT2A-R cells, we identified RUNX2 as a direct target of the KMT2A chimeras, where it reciprocally bound the KMT2A promoter, establishing a regulatory feed-forward mechanism. Notably, RUNX2 was required for survival of immature and KMT2A-R T-ALL cells in vitro and in vivo. We report direct transcriptional regulation of CXCR4 signaling by RUNX2, thereby promoting chemotaxis, adhesion, and homing to medullary and extramedullary sites. RUNX2 enabled these energy-demanding processes by increasing metabolic activity in T-ALL cells through positive regulation of both glycolysis and oxidative phosphorylation. Concurrently, RUNX2 upregulation increased mitochondrial dynamics and biogenesis in T-ALL cells. Finally, as a proof of concept, we demonstrate that immature and KMT2A-R T-ALL cells were vulnerable to pharmacological targeting of the interaction between RUNX2 and its cofactor CBFβ. In conclusion, we show that RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL through concomitant regulation of tumor metabolism and leukemic cell migration.
    Mesh-Begriff(e) Animals ; Cell Line, Tumor ; Chemotaxis, Leukocyte ; Child ; Core Binding Factor Alpha 1 Subunit/genetics ; Core Binding Factor Alpha 1 Subunit/metabolism ; Core Binding Factor beta Subunit/metabolism ; Disease Progression ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Neoplastic ; Gene Rearrangement ; Hematopoiesis ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Humans ; In Vitro Techniques ; Mice ; Myeloid-Lymphoid Leukemia Protein/genetics ; Myeloid-Lymphoid Leukemia Protein/metabolism ; Organelle Biogenesis ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptors, CXCR4/metabolism ; Signal Transduction
    Chemische Substanzen CBFB protein, human ; CXCR4 protein, human ; Core Binding Factor Alpha 1 Subunit ; Core Binding Factor beta Subunit ; KMT2A protein, human ; RNA, Messenger ; RUNX2 protein, human ; Receptors, CXCR4 ; Myeloid-Lymphoid Leukemia Protein (149025-06-9) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43)
    Sprache Englisch
    Erscheinungsdatum 2021-02-08
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI141566
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Ua VI Zs.184: Hefte anzeigen Standort:
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