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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\u03b4\/\u03b5 (CK1\u03b4\/\u03b5) is a promising CLL treatment strategy. Herein, we elucidate the molecular and cellular mechanisms mediating CK1\u03b4\/\u03b5 inhibition efficacy in CLL. Using an in vivo E\u00b5\u2010TCL1 adoptive transfer model, we showed that CK1\u03b4\/\u03b5 inhibition caused CLL cell accumulation at the S\/G2 phase in a cell\u2010intrinsic mode. Furthermore, CK1\u03b4\/\u03b5 inhibition led to a T\u2010cell decrease in lymph nodes (LNs). Using primary CLL cells and a system mimicking the LN microenvironment in vitro, we demonstrated that CK1\u03b4\/\u03b5 inhibition interfered with multiple pro\u2010survival mechanisms provided by the microenvironment, most notably with the nuclear factor \u03ba B (NF\u03baB) pathway. NF\u03baB acts downstream of the T\u2010cell\u2010mediated CD40L:CD40 stimulus, and indeed, CK1\u03b4\/\u03b5 inhibition efficiently blocked the proliferation of primary CLL triggered by CD40L across multiple patient groups, with lower efficacy in patients with\n                    <jats:italic>TP53<\/jats:italic>\n                    defects. We propose that CK1\u03b4\/\u03b5 inhibitors act in the multiple\u2010hit mode, striking both intrinsically via direct interference with cell cycle machinery and extrinsically via inhibition of multiple pro\u2010proliferative stimuli.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70343","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T14:29:23Z","timestamp":1774362563000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Casein kinase 1\u03b4\/\u03b5 inhibition suppresses CLL proliferation through cell\u2010intrinsic and microenvironmental mechanisms"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6226-9086","authenticated-orcid":false,"given":"Antonia","family":"Mikulova","sequence":"first","affiliation":[{"name":"Department of Experimental Biology, Faculty of Science Masaryk University Brno Czech 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