Casein kinase 1δ/ε inhibition suppresses CLL proliferation 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 still incurable in many cases; therefore, there is an urgent need to develop novel therapeutic options. We have shown earlier that inhibition of casein kinase 1δ/ε (CK1δ/ε) is a promising CLL treatment strategy. Herein, we elucidate the molecular and cellular mechanisms mediating CK1δ/ε inhibition efficacy in CLL. Using an in vivo Eµ-TCL1 adoptive transfer model, we showed that CK1δ/ε inhibition caused CLL cell accumulation at the S/G2 phase in a cell-intrinsic mode. Furthermore, CK1δ/ε inhibition led to a T-cell decrease in lymph nodes (LNs). Using primary CLL cells and a system mimicking the LN microenvironment in vitro, we demonstrated that CK1δ/ε inhibition interfered with multiple pro-survival mechanisms provided by the microenvironment, most notably with the nuclear factor κ B (NFκB) pathway. NFκB acts downstream of the T-cell-mediated CD40L:CD40 stimulus, and indeed, CK1δ/ε inhibition efficiently blocked the proliferation of primary CLL triggered by CD40L across multiple patient groups, with lower efficacy in patients with TP53 defects. We propose that CK1δ/ε inhibitors act in the multiple-hit mode, striking both intrinsically via direct interference with cell cycle machinery and extrinsically via inhibition of multiple pro-proliferative stimuli.