Publication details
Casein kinase 1δ/ε inhibition suppresses CLL proliferation through cell-intrinsic and microenvironmental mechanisms
| Authors | |
|---|---|
| Year of publication | 2026 |
| Type | Article in Periodical |
| Magazine / Source | HemaSphere |
| MU Faculty or unit | |
| Citation | |
| web | https://onlinelibrary.wiley.com/doi/10.1002/hem3.70343 |
| Doi | https://doi.org/10.1002/hem3.70343 |
| Keywords | Chronic Lymphocytic Leukemia (CLL); Casein kinase 1 (CK1?/?); CK1 inhibitors; NF-?B; Tumor microenvironment; Eµ-TCL1 model; Cell cycle |
| Attached files | |
| Description | 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 1 delta/epsilon (CK1 delta/epsilon) is a promising CLL treatment strategy. Herein, we elucidate the molecular and cellular mechanisms mediating CK1 delta/epsilon inhibition efficacy in CLL. Using an in vivo E & micro;-TCL1 adoptive transfer model, we showed that CK1 delta/epsilon inhibition caused CLL cell accumulation at the S/G2 phase in a cell-intrinsic mode. Furthermore, CK1 delta/epsilon 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 CK1 delta/epsilon inhibition interfered with multiple pro-survival mechanisms provided by the microenvironment, most notably with the nuclear factor kappa B (NF kappa B) pathway. NF kappa B acts downstream of the T-cell-mediated CD40L:CD40 stimulus, and indeed, CK1 delta/epsilon 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 CK1 delta/epsilon 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. |
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