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.

Center of Molecular Biology and Gene Therapy Department of Internal Medicine Hematology Oncology University Hospital Brno and Medical Faculty Masaryk University Brno Czech Republic

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Chemistry and Toxicology Veterinary Research Institute Brno Czech Republic

Department of Histology and Embryology Faculty of Medicine Masaryk University 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

International Clinical Research Center Center for Biomolecular and Cellular Engineering St Anne's University Hospital in Brno Brno Czech Republic

Paracelsus Medical University Salzburg Austria; and

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