Transkripční faktor FoxO1 v adaptaci chronické lymfocytární leukémie na cílenou léčbu.

Investor logo
Investor logo

Warning

This publication doesn't include Faculty of Economics and Administration. It includes Central European Institute of Technology. Official publication website can be found on muni.cz.
Title in English Transcription factor FoxO1 in adaptation of chronic lymphocytic leukemia to targeted therapy.
Authors

ONDRIŠOVÁ Laura ŠEDA Václav HOFERKOVÁ Eva KOŠŤÁLOVÁ Lenka HLAVÁČ Kryštof PAVELKOVÁ Petra MLADONICKÁ PAVLASOVÁ Gabriela FARIA ZENI Pedro PLEVOVÁ Karla FILIP Daniel DOUBEK Michael MAYER Jiří MRÁZ Marek

Year of publication 2023
Type Conference abstract
MU Faculty or unit

Central European Institute of Technology

Citation
Attached files
Description B-cell receptor signaling pathway inhibitors (so-called BCR inhibitors) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Among their mechanisms of action is the blocking of important interactions of leukemic cells in the microenvironment of the lymphatic organs, leading to the leaching of leukemic cells into the peripheral blood, i.e. to lymphocytosis, where they survive for a surprisingly long time. The mechanism of this early adaptation to BCR inhibitors is not yet clear. We have previously shown that the transcription factor FoxO1 contributes to the survival of cells in the peripheral blood of CLL patients and is also involved in the migration of CLL cells back into the microenvironment. Here we show that FoxO1 levels are increased after treatment with ibrutinib, a BCR inhibitor targeting the BTK kinase. Analysis of the binding of FoxO1 to the human genome by the CUT&RUN method revealed its higher activity in the MEC1 cell line exposed to ibrutinib in vitro. A study of signaling pathways regulated by FoxO1 and subsequent analysis of paired primary samples from patients treated with ibrutinib revealed that increased FoxO1 activity leads to increased levels of the protein Rictor, which in turn activates the Akt kinase in the mTORC2 complex, a molecule important for survival. CLL cells. Increased levels of activated Akt were associated with higher and longer ibrutinib-induced lymphocytosis. Inhibition of FoxO1 resulted in reduced viability and proliferation of CLL cells, and this effect was potentiated by the combination of FoxO1 inhibitor with ibrutinib.
Related projects:

You are running an old browser version. We recommend updating your browser to its latest version.