REGULATION OF BCR SIGNALLING BY DNA DAMAGE RESPONSE AND P53 PROTEIN

Doctoral study program: Molecular Medicine

Research area: Cancer biology

Consultant: Marek Mraz, MD, Ph.D.

We are looking for a motivated PhD student that would like to work on the following project funded by the ERC (European Research Council) Starting grant. The variable clinical course of several B cell malignancies largely depends on p53 functionality and B-cell receptor (BCR) signalling propensity; however, it is unclear if there is any crosstalk between these pathways. We showed for the first time that there is a connection between p53 pathway and regulation of BCR signalling (Cerna et al., Leukemia 2018). We described that DNA damage response (DDR) activation leads to down-modulating the transcriptional factor FOXP1, which functions as a positive BCR signalling. It seems that the low FOXP1 levels limit BCR signalling partially via allowing for upregulation of a CD22 cell-surface, whose intracellular part serves as a docking site for phosphatases that limit BCR activation on the cell membrane. The student will further explore the connection between DNA damage response and the BCR signalling regulation. Additionally, the p53 aberration could also affect the basal levels of CD22/phosphatases, and thus contribute to the “tonic” BCR signalling, and general aggressiveness of the B cells. In vitro studies using CRISPR technology and inducible shRNAs for p53 will be conducted. Additionally, we have collected over 100 samples obtained during the administration of chemo-immuno therapy in B-cell chronic lymphocytic leukaemia (CLL) patients, and these can be used to validate the in vitro observations.

Recommended literature:

Cerna et al. MicroRNA miR-34a Downregulates FOXP1 During DNA Damage Response to Limit BCR Signalling in Chronic Lymphocytic Leukaemia B Cells. Leukemia, 2019, https://doi.org/10.1038/s41375-018-0230-x.

 Cerna and Mraz P53 Limits B Cell Receptor (BCR) Signalling: A New Role for miR-34a and FOXP1. Oncotarget, 2018, https://doi.org/10.18632/oncotarget.26376.

Kipps et al. Chronic Lymphocytic Leukaemia. Nature Reviews Disease Primers, 2017, https://doi.org/10.1038/nrdp.2016.96.

Requirements on candidates:

• Master’s degree in Molecular biology, Biochemistry, or similar field of study
• Experience of working in a laboratory
• The ability of collective work as well as independent project planning
• Desire to learn new things

Information on the supervisor:

Nine years of experience in chronic lymphocytic leukemia research, first-author publications in Q1 journals (Boudny, Haematologica 2019; Boudny, Cancer Treatment Reviews 2020; total 29 citations), internship at the University of Birmingham in research group of Tatjana Stankovic, supervision of students (supervisor of 1 diploma and 2 bachelor students, co-supervisor of 1 diploma student). Extensive experience in the fields of cancer biology, hematology, immunology.

More at: https://is.muni.cz/auth/person/393305.

More information about the research group: http://mrazlab.ceitec.cz/