Casein kinase 1δ/ε inhibition suppresses CLL through cell-intrinsic and microenvironmental mechanisms

Chronic lymphocytic leukemia (CLL) is a consequence of pathological B cell accumulation in blood and lymphoid organs. Due to high refractoriness, CLL is considered incurable which calls for novel therapeutic options. Previously, we showed casein kinase 1δ/ε (CK1δ/ε) inhibition prolonged survival of Eµ-TCL1 mice with CLL-like disease. Herein, we elucidate mechanisms mediating CK1δ/ε inhibition efficacy in CLL suppression. Using in vivo Eµ-TCL1 adoptive transfer (AT) model, we showed CK1δ/ε inhibition mediated cell cycle slowdown and CLL cell accumulation at S/G2 interface. This observation was validated using multiple CLL cell lines and EdU/Click-iT reaction applied in vivo. Furthermore, we showed CK1δ/ε inhibition led to T cell decrease in lymph nodes (LN). Using system mimicking LN microenvironment in vitro, we observed CK1δ/ε inhibition triggered downregulation of nuclear factor κ B (NFκB) pathway that acts downstream of T-cell-mediated CD40L:CD40 stimulus, inducing CLL cell proliferation. Finally, we showed CK1δ/ε inhibition counteracted proliferation of CLL cells from wide range of patients, with lower efficacy only in patients bearing TP53 defects.