Abstract 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.
Mikulová et al. (Sun,) studied this question.