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Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F18%3A00492501" target="_blank" >RIV/68081707:_____/18:00492501 - isvavai.cz</a>

  • Výsledek na webu

    <a href="http://dx.doi.org/10.1182/blood-2017-05-786947" target="_blank" >http://dx.doi.org/10.1182/blood-2017-05-786947</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1182/blood-2017-05-786947" target="_blank" >10.1182/blood-2017-05-786947</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia

  • Popis výsledku v původním jazyce

    Casein kinase 1 delta/epsilon (CK1 delta/epsilon) is a key component of noncanonical Wnt signaling pathways, which were shown previously to drive pathogenesis of chronic lymphocytic leukemia (CLL). In this study, we investigated thoroughly the effects of CK1 delta/epsilon inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using 2 murine model systems based on the E mu-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resembles closely human CLL. We can demonstrate that the CK1 delta/epsilon inhibitor PF-670462 significantly blocks microenvironmental interactions (chemotaxis, invasion and communication with stromal cells) in primary CLL cells in all major subtypes of CLL. In the mouse models, CK1 inhibition slows down accumulation of leukemic cells in the peripheral blood and spleen and prevents onset of anemia. As a consequence, PF-670462 treatment results in a significantly longer overall survival. Importantly, CK1 inhibition has synergistic effects to the B-cell receptor (BCR) inhibitors such as ibrutinib in vitro and significantly improves ibrutinib effects in vivo. Mice treated with a combination of PF-670462 and ibrutinib show the slowest progression of disease and survive significantly longer compared with ibrutinib-only treatment when the therapy is discontinued. In summary, this preclinical testing of CK1 delta/epsilon inhibitor PF-670462 demonstrates that CK1 may serve as a novel therapeutic target in CLL, acting in synergy with BCR inhibitors. Our work provides evidence that targeting CK1 can represent an alternative or addition to the therapeutic strategies based on BCR signaling and antiapoptotic signaling (BCL-2) inhibition.

  • Název v anglickém jazyce

    Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia

  • Popis výsledku anglicky

    Casein kinase 1 delta/epsilon (CK1 delta/epsilon) is a key component of noncanonical Wnt signaling pathways, which were shown previously to drive pathogenesis of chronic lymphocytic leukemia (CLL). In this study, we investigated thoroughly the effects of CK1 delta/epsilon inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using 2 murine model systems based on the E mu-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resembles closely human CLL. We can demonstrate that the CK1 delta/epsilon inhibitor PF-670462 significantly blocks microenvironmental interactions (chemotaxis, invasion and communication with stromal cells) in primary CLL cells in all major subtypes of CLL. In the mouse models, CK1 inhibition slows down accumulation of leukemic cells in the peripheral blood and spleen and prevents onset of anemia. As a consequence, PF-670462 treatment results in a significantly longer overall survival. Importantly, CK1 inhibition has synergistic effects to the B-cell receptor (BCR) inhibitors such as ibrutinib in vitro and significantly improves ibrutinib effects in vivo. Mice treated with a combination of PF-670462 and ibrutinib show the slowest progression of disease and survive significantly longer compared with ibrutinib-only treatment when the therapy is discontinued. In summary, this preclinical testing of CK1 delta/epsilon inhibitor PF-670462 demonstrates that CK1 may serve as a novel therapeutic target in CLL, acting in synergy with BCR inhibitors. Our work provides evidence that targeting CK1 can represent an alternative or addition to the therapeutic strategies based on BCR signaling and antiapoptotic signaling (BCL-2) inhibition.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    30205 - Hematology

Návaznosti výsledku

  • Projekt

  • Návaznosti

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Ostatní

  • Rok uplatnění

    2018

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    Blood

  • ISSN

    1528-0020

  • e-ISSN

  • Svazek periodika

    131

  • Číslo periodika v rámci svazku

    11

  • Stát vydavatele periodika

    CZ - Česká republika

  • Počet stran výsledku

    13

  • Strana od-do

    1206-1218

  • Kód UT WoS článku

    000430687500009

  • EID výsledku v databázi Scopus