| JANOVSKÁ, Pavlína, Jan VERNER, Jiří KOHOUTEK, Lenka BRYJOVÁ, Michaela GREGOROVÁ, Marta DZIMKOVÁ, Hana ŠKABRAHOVÁ, Tomasz Witold RADASZKIEWICZ, Petra OVESNÁ, Olga VONDÁLOVÁ BLANÁŘOVÁ, Tereza NĚMCOVÁ, Zuzana HOFEROVA, Kateřina VAŠÍČKOVÁ, Lucie NESVADBOVÁ, Alexander EGLE, Šárka PAVLOVÁ, Lucie POPPOVÁ, Karla PLEVOVÁ, Šárka POSPÍŠILOVÁ and Vítězslav BRYJA. Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia. Blood. Washington DC, USA: American Society of Hematology, 2018, vol. 131, No 11, p. 1206-1218. ISSN 0006-4971. Available from: https://dx.doi.org/10.1182/blood-2017-05-786947. |
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@article{1420883,
author = {Janovská, Pavlína and Verner, Jan and Kohoutek, Jiří and Bryjová, Lenka and Gregorová, Michaela and Dzimková, Marta and Škabrahová, Hana and Radaszkiewicz, Tomasz Witold and Ovesná, Petra and Vondálová Blanářová, Olga and Němcová, Tereza and Hoferova, Zuzana and Vašíčková, Kateřina and Nesvadbová, Lucie and Egle, Alexander and Pavlová, Šárka and Poppová, Lucie and Plevová, Karla and Pospíšilová, Šárka and Bryja, Vítězslav},
article_location = {Washington DC, USA},
article_number = {11},
doi = {http://dx.doi.org/10.1182/blood-2017-05-786947},
keywords = {casein kinase 1; inhibitor; chronic lymphocytic leukemia; microenvironmental interactions},
language = {eng},
issn = {0006-4971},
journal = {Blood},
title = {Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia},
url = {http://dx.doi.org/10.1182/blood-2017-05-786947},
volume = {131},
year = {2018}
}
TY - JOUR
ID - 1420883
AU - Janovská, Pavlína - Verner, Jan - Kohoutek, Jiří - Bryjová, Lenka - Gregorová, Michaela - Dzimková, Marta - Škabrahová, Hana - Radaszkiewicz, Tomasz Witold - Ovesná, Petra - Vondálová Blanářová, Olga - Němcová, Tereza - Hoferova, Zuzana - Vašíčková, Kateřina - Nesvadbová, Lucie - Egle, Alexander - Pavlová, Šárka - Poppová, Lucie - Plevová, Karla - Pospíšilová, Šárka - Bryja, Vítězslav
PY - 2018
TI - Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia
JF - Blood
VL - 131
IS - 11
SP - 1206-1218
EP - 1206-1218
PB - American Society of Hematology
SN - 00064971
KW - casein kinase 1
KW - inhibitor
KW - chronic lymphocytic leukemia
KW - microenvironmental interactions
UR - http://dx.doi.org/10.1182/blood-2017-05-786947
N2 - 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.
ER -
JANOVSKÁ, Pavlína, Jan VERNER, Jiří KOHOUTEK, Lenka BRYJOVÁ, Michaela GREGOROVÁ, Marta DZIMKOVÁ, Hana ŠKABRAHOVÁ, Tomasz Witold RADASZKIEWICZ, Petra OVESNÁ, Olga VONDÁLOVÁ BLANÁŘOVÁ, Tereza NĚMCOVÁ, Zuzana HOFEROVA, Kateřina VAŠÍČKOVÁ, Lucie NESVADBOVÁ, Alexander EGLE, Šárka PAVLOVÁ, Lucie POPPOVÁ, Karla PLEVOVÁ, Šárka POSPÍŠILOVÁ and Vítězslav BRYJA. Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia. \textit{Blood}. Washington DC, USA: American Society of Hematology, 2018, vol.~131, No~11, p.~1206-1218. ISSN~0006-4971. Available from: https://dx.doi.org/10.1182/blood-2017-05-786947.
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