ROLE OF FOXO1 TRANSCRIPTION FACTOR IN B-CELL MALIGNANCIES

The project is focused on FoxO1 transcription factor and its role in the pathophysiology of chronic lymphocytic leukemia (CLL). Although the therapy of CLL has made several remarkable improvements, the disease still remains incurable. Current therapeutic approaches mainly include the use of so-called B-cell receptor signaling inhibitors (ibrutinib, idelalisib) leading to disruption of pro-survival and pro-proliferative interactions in immune niches, and the use of venetoclax, which “inhibits” BCL2 anti-apoptotic protein. We have previously described that FoxO1 protein is crucial for homing capacity of CLL cell to immune niches and tonic Akt activity supporting the survival of malignant B cells (Seda et al…Mraz, Blood, 2021). Results from the FoxO1 knockout CLL cell line suggest that FoxO1 is involved in adaptation to targeted therapy (our unpublished data). The project aims to investigate further the role of FoxO1 in microenvironmental interactions, regulation of apoptosis, and adaptation to targeted therapy. The student will use technics such as genome editing (CRISPR), CHIP seq, RNA sequencing, drug testing in vitro, primary CLL samples obtained on therapy, and functional studies with various in vitro and in vivo models. The research is also relevant for the pre-clinical development of novel drugs and their combinations (several patents submitted by the lab).

Recommended literature: 

• Seda V. et al….Mraz. FoxO1-GAB1 Axis Regulates Homing Capacity and Tonic AKT Activity in Chronic Lymphocytic Leukemia. Blood, 2021, https://doi.org/10.1182/blood.2020008101.
• Ondrisova L, Mraz M. Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancie. Front Oncol. 2020 Oct 26;10:591577.
• Kipps et al. Chronic lymphocytic leukaemia. Nat Rev 2017 https://pubmed.ncbi.nlm.nih.gov/28102226/
• Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells.  Eur J Haematol. 2015 Mar;94(3):193-205. doi: 10.1111/ejh.12427. Epub 2014 Sep 13. PMID: 25080849 Review.

Requirements on candidates:

• Motivated smart people that have the “drive” to work independently, but also willing to learn from other people in the lab and collaborate.
• Candidates should have a master’s degree in Molecular biology, Biochemistry, or similar field and have deep interest in molecular biology and cancer cell biology.