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Casein Kinase 1 is a Therapeutic Target in Chronic Lymphocytic Leukemia

Pavlina Janovska, Jan Verner, Jiri Kohoutek, Lenka Bryjova, Michaela Gregorova, Marta Dzimkova, Hana Skabrahova, Tomasz Radaszkiewicz, Petra Ovesna, Olga Vondalova Blanarova, Tereza Nemcova, Zuzana Hoferova, Katerina Vasickova, Lucie Smyckova, Alexander Egle, Sarka Pavlova, Lucie Poppova, Karla Plevova, Sarka Pospisilova and Vitezslav Bryja

Key points

  • Casein kinase 1 (CK1) inhibition significantly blocks microenvironmental interactions of CLL cells.

  • CK1 inhibition slows down development of CLL-like disease in the Eμ-TCL1 mouse model.

Abstract

Casein kinase (CK) 1δ/ε is a key component of non-canonical 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 two murine model systems based on the Eµ-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resemble closely the human CLL. We can demonstrate that 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 effect to the BCR inhibitors such as ibrutinib in vitro and significantly improves ibrutinib effects in vivo. Mice treated by combination of PF-670462 and ibrutinib show the slowest progression of the disease and survive significantly longer compared to 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 B-cell receptor (BCR) signaling and anti-apoptotic signaling (BCL-2) inhibition.

  • Submitted May 25, 2017.
  • Accepted January 1, 2018.