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Berlin Brandenburg

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  • 1
    Language: English
    In: Blood, 21 December 2017, Vol.130(25), pp.2774-2785
    Description: Platelets, anucleated megakaryocyte (MK)-derived cells, play a major role in hemostasis and arterial thrombosis. Although protein kinase casein kinase 2 (CK2) is readily detected in MKs and platelets, the impact of CK2-dependent signaling on MK/platelet (patho-)physiology has remained elusive. The present study explored the impact of the CK2 regulatory β-subunit on platelet biogenesis and activation. MK/platelet-specific genetic deletion of CK2β ( ) in mice resulted in a significant macrothrombocytopenia and an increased extramedullar megakaryopoiesis with an enhanced proportion of premature platelets. Although platelet life span was only mildly affected, MK displayed an abnormal microtubule structure with a drastically increased fragmentation within bone marrow and a significantly reduced proplatelet formation in vivo. In platelets, tubulin polymerization was disrupted, resulting in an impaired thrombopoiesis and an abrogated inositol 1,4,5-triphosphate receptor-dependent intracellular calcium (Ca) release. Presumably due to a blunted increase in the concentration of cytosolic Ca, activation-dependent increases of α and dense-granule secretion and integrin αβ activation, and aggregation were abrogated in platelets. Accordingly, thrombus formation and stabilization under high arterial shear rates were significantly diminished, and thrombotic vascular occlusion in vivo was significantly blunted in mice, accompanied by a slight prolongation of bleeding time. Following transient middle cerebral artery occlusion, mice displayed significantly reduced cerebral infarct volumes, developed significantly less neurological deficits, and showed significantly better outcomes after ischemic stroke than mice. The present observations reveal CK2β as a novel powerful regulator of thrombopoiesis, Ca-dependent platelet activation, and arterial thrombosis in vivo.
    Keywords: Platelet Activation ; Thrombopoiesis ; Casein Kinase II -- Physiology ; Peptide Fragments -- Physiology ; Thrombosis -- Pathology
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 2
    Language: English
    In: Blood, 19 July 2018, Vol.132(3), pp.307-320
    Description: Heat shock protein 90 (HSP90) stabilizes many client proteins, including the BCR-ABL1 oncoprotein. BCR-ABL1 is the hallmark of chronic myeloid leukemia (CML) in which treatment-free remission (TFR) is limited, with clinical and economic consequences. Thus, there is an urgent need for novel therapeutics that synergize with current treatment approaches. Several inhibitors targeting the N-terminal domain of HSP90 are under investigation, but side effects such as induction of the heat shock response (HSR) and toxicity have so far precluded their US Food and Drug Administration approval. We have developed a novel inhibitor (aminoxyrone [AX]) of HSP90 function by targeting HSP90 dimerization via the C-terminal domain. This was achieved by structure-based molecular design, chemical synthesis, and functional preclinical in vitro and in vivo validation using CML cell lines and patient-derived CML cells. AX is a promising potential candidate that induces apoptosis in the leukemic stem cell fraction (CD34CD38) as well as the leukemic bulk (CD34CD38) of primary CML and in tyrosine kinase inhibitor (TKI)-resistant cells. Furthermore, BCR-ABL1 oncoprotein and related pro-oncogenic cellular responses are downregulated, and targeting the HSP90 C terminus by AX does not induce the HSR in vitro and in vivo. We also probed the potential of AX in other therapy-refractory leukemias. Therefore, AX is the first peptidomimetic C-terminal HSP90 inhibitor with the potential to increase TFR in TKI-sensitive and refractory CML patients and also offers a novel therapeutic option for patients with other types of therapy-refractory leukemia because of its low toxicity profile and lack of HSR.
    Keywords: Animals–Chemistry ; Antineoplastic Agents–Pharmacology ; Binding Sites–Drug Effects ; Biomarkers, Tumor–Drug Effects ; Cell Cycle–Drug Effects ; Cell Line, Tumor–Antagonists & Inhibitors ; Cell Survival–Chemistry ; Disease Models, Animal–Antagonists & Inhibitors ; Drug Resistance, Neoplasm–Chemistry ; Fusion Proteins, Bcr-Abl–Metabolism ; Hsp90 Heat-Shock Proteins–Drug Effects ; Heat-Shock Response–Chemistry ; Humans–Pharmacology ; Imatinib Mesylate–Drug Therapy ; Leukemia, Myelogenous, Chronic, BCR-Abl Positive–Metabolism ; Mice–Chemistry ; Models, Molecular–Pharmacology ; Molecular Conformation–Drug Effects ; Molecular Structure–Drug Effects ; Protein Binding–Drug Effects ; Protein Interaction Domains and Motifs–Drug Effects ; Protein Kinase Inhibitors–Drug Effects ; Protein Multimerization–Drug Effects ; Spectrum Analysis–Drug Effects ; Structure-Activity Relationship–Drug Effects ; Xenograft Model Antitumor Assays–Drug Effects ; Abridged ; Antineoplastic Agents ; Biomarkers, Tumor ; Hsp90 Heat-Shock Proteins ; Protein Kinase Inhibitors ; Imatinib Mesylate ; Fusion Proteins, Bcr-Abl;
    ISSN: 00064971
    E-ISSN: 1528-0020
    Library Location Call Number Volume/Issue/Year Availability
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