Casein kinase 1 is a therapeutic target in chronic lymphocytic
leukemia

J 2018

Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia

JANOVSKÁ, Pavlína, Jan VERNER, Jiří KOHOUTEK, Lenka BRYJOVÁ, Michaela GREGOROVÁ et. al.

Basic information

Original name

Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia

Authors

JANOVSKÁ, Pavlína (203 Czech Republic, belonging to the institution), Jan VERNER (203 Czech Republic, belonging to the institution), Jiří KOHOUTEK (203 Czech Republic), Lenka BRYJOVÁ (203 Czech Republic, belonging to the institution), Michaela GREGOROVÁ (203 Czech Republic, belonging to the institution), Marta DZIMKOVÁ (703 Slovakia), Hana ŠKABRAHOVÁ (203 Czech Republic, belonging to the institution), Tomasz Witold RADASZKIEWICZ (616 Poland, belonging to the institution), Petra OVESNÁ (203 Czech Republic, belonging to the institution), Olga VONDÁLOVÁ BLANÁŘOVÁ (203 Czech Republic, belonging to the institution), Tereza NĚMCOVÁ (203 Czech Republic, belonging to the institution), Zuzana HOFEROVA (203 Czech Republic), Kateřina VAŠÍČKOVÁ (203 Czech Republic, belonging to the institution), Lucie NESVADBOVÁ (203 Czech Republic, belonging to the institution), Alexander EGLE (40 Austria), Šárka PAVLOVÁ (203 Czech Republic, belonging to the institution), Lucie POPPOVÁ (203 Czech Republic, belonging to the institution), Karla PLEVOVÁ (203 Czech Republic, belonging to the institution), Šárka POSPÍŠILOVÁ (203 Czech Republic, belonging to the institution) and Vítězslav BRYJA (203 Czech Republic, guarantor, belonging to the institution)

Edition

Blood, Washington DC, USA, American Society of Hematology, 2018, 0006-4971

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30107 Medicinal chemistry

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 16.601

RIV identification code

RIV/00216224:14310/18:00103027

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1182/blood-2017-05-786947

UT WoS

000430687500009

Keywords in English

casein kinase 1; inhibitor; chronic lymphocytic leukemia; microenvironmental interactions

Abstract

V originále

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.

Links

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/E/0102/2017, interní kód MU

Name: Casein Kinase 1 is a Therapeutic Target in Chronic Lymphocytic Leukemia

Investor: Masaryk University, Promoting quality excellence

MUNI/31/53609/2016, interní kód MU

Name: Analýza nových inhibitorů kasein kinázy 1 pro léčbu chronické lymfocytární leukémie

Investor: Masaryk University

NV15-29793A, research and development project

Name: Analýza Wnt/PCP jako nástroj pro lepší management chronické lymfocytární leukémie

Citovat

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.

@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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