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

• Autoři: MIKULOVÁ Antónia; PLEŠINGEROVÁ Hana; CHORVÁTOVÁ Michaela; KEBKOVÁ Pavlína; BARTOŠÍKOVÁ Jana; PROCHÁZKOVÁ SCHRUMPFOVÁ Petra; VERNER Jan; MULIDRÁN Dominik; ČADA Štěpán; VONDÁLOVÁ BLANÁŘOVÁ Olga; KOLČÁKOVÁ Nela; LOJA Tomáš; KURUCOVÁ Terézia; HOFERKOVÁ Eva; TICHÝ Boris; KOTAŠKOVÁ Jana; MRÁZ Marek; KUBALA Lukáš; JANOVSKÁ Pavlína; BRYJA Vítězslav
• Rok publikování: 2026
• Druh: Článek v odborném periodiku
• Časopis / Zdroj: HemaSphere
• Fakulta / Pracoviště MU: Přírodovědecká fakulta
• www: https://onlinelibrary.wiley.com/doi/10.1002/hem3.70343
• Doi: https://doi.org/10.1002/hem3.70343
• Klíčová slova: Chronic Lymphocytic Leukemia (CLL); Casein kinase 1 (CK1?/?); CK1 inhibitors; NF-?B; Tumor microenvironment; Eµ-TCL1 model; Cell cycle

Přiložené soubory

• Casein_kinase_1__inhibition_suppresses_CLL_proliferation_through_cell-intrinsic_and_microenvironmental_mechanisms.pdf

• Popis: 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.

Související projekty

• Národní ústav pro výzkum rakoviny
• ROR1-pozitivní b-buňky v periferní krvi zdravých dárců a jejich souvislost s rozvojem chronické lymfocytární leukémie
• Vývoj modelů pro studium mikroprostředí a terapeutické rezistence u B buněčných malignit