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Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia
P. Janovska, J. Verner, J. Kohoutek, L. Bryjova, M. Gregorova, M. Dzimkova, H. Skabrahova, T. Radaszkiewicz, P. Ovesna, O. Vondalova Blanarova, T. Nemcova, Z. Hoferova, K. Vasickova, L. Smyckova, A. Egle, S. Pavlova, L. Poppova, K. Plevova, S....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
NV15-29793A
MZ0
CEP - Centrální evidence projektů
Digitální knihovna NLK
Plný text - Článek
Zdroj
NLK
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od 1946 do Před 1 rokem
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od 1946 do Před 1 rokem
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od 1946-01-01
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- MeSH
- chronická lymfatická leukemie farmakoterapie enzymologie genetika MeSH
- HEK293 buňky MeSH
- kaseinkinasa Idelta antagonisté a inhibitory genetika metabolismus MeSH
- kaseinkinasa Iepsilon antagonisté a inhibitory genetika metabolismus MeSH
- lékové transportní systémy MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny antagonisté a inhibitory genetika metabolismus MeSH
- pyrazoly farmakologie MeSH
- pyrimidiny farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Casein kinase 1δ/ε (CK1δ/ε) 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 CK1δ/ε inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using 2 murine model systems based on the Eµ-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resembles closely human CLL. We can demonstrate that the CK1δ/ε 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 CK1δ/ε 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.
Department of Chemistry and Toxicology Veterinary Research Institute Brno Czech Republic
Institute of Biophysics Academy of Sciences of the Czech Republic Brno Czech Republic
Institute of Biostatistics and Analyses Masaryk University Brno Czech Republic
Institute of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic
Citace poskytuje Crossref.org
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