Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia

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>

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30205 - Hematology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2018

Kód důvěrnosti údajů

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

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

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