Overview
Doctoral study program: Biomedical Sciences
Specialization: Molecular Medicine
Form of study: doctoral full-time
Department: Microenvironment of Immune Cells – prof. Marek Mraz research group, CEITEC MU and Dept of Internal Medicine Faculty Hospital Brno
Supervisor: Mgr. Veronika Šandová, Ph.D.
Topic title
THERAPY-INDUCED CHANGES IN CD20 EXPRESSION AND MICROENVIRONMENTAL INTERACTIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA.
Annotation:
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western world. Dysregulation of B cell receptor (BCR) signaling and microenvironmental interactions within immune niches plays a crucial role in CLL pathophysiology by providing survival and proliferation signals. BCR inhibitors targeting key BCR-associated kinases, such as BTK and PI3K delta, are highly effective as single agents in CLL but are not curative. To enhance their efficacy, BTK/PI3K inhibitors are commonly combined with anti-CD20 monoclonal antibodies. We suppose that BTK inhibitors (BTKi) disrupt the regulation of CD20 transcription, leading to a reduction in CD20 expression on CLL cells, which directly impacts the efficacy of anti-CD20 antibodies. We aim to elucidate the mechanisms underlying CD20 regulation in the context of BTKi treatment. We hypothesize that BTKi affect the CD20 transcription and we will investigate the specific mechanisms. CD20 levels have direct implications for combinatorial therapies, as anti-CD20 antibodies and anti-CD20 CAR T-cells form the backbone of treatment for mature B cell malignancies. The project focuses on elucidating changes in gene expression within the tumor microenvironment of chronic lymphocytic leukemia (CLL) in response to BTK inhibitors and investigates the impact of BTK inhibitor therapy on IL4 signaling as well as other signaling pathways, and its consequences for the regulation of the therapeutically relevant molecule CD20. The results of this project may contribute to a better understanding of the pathophysiology of B cell malignancies and the improvement of CLL treatment.
Recommended literature:
1) Sandova V et al. IL4-STAT6 signaling induces CD20 in chronic lymphocytic leukemia and this axis is repressed by PI3K delta inhibitor idelalisib. Haematologica. 2021;106(11):2995-2999. https://pmc.ncbi.nlm.nih.gov/articles/PMC8561290/
2) Pavlasova G*, Borsky M*, Svobodova V* et al. Rituximab primarily targets an intra-clonal BCR signaling proficient CLL subpopulation characterized by high CD20 levels. Leukemia. 2018; 32(9):2028-2031.
https://pubmed.ncbi.nlm.nih.gov/30030508/
3) Sharma S, … Sandova V et al. miR-29 modulates CD40 signaling in chronic lymphocytic leukemia by targeting TRAF4: an axis affected by BCR inhibitors. Blood. 2021;137(18):2481-2494.
https://pubmed.ncbi.nlm.nih.gov/33171493/
4) Pavlasova GM and Mraz M. The regulation and function of CD20: an « enigma » of B-cell biology and targeted therapy. Haematologica. 2020; 105(6):1494-1506.
https://pubmed.ncbi.nlm.nih.gov/32482755/
5) Burger JA. Targeting the microenvironment in chronic lymphocytic leukemia is changing the therapeutic landscape. Curr Opin Oncol. 2012; 24(6):634-9.
https://pubmed.ncbi.nlm.nih.gov/22960555/
Research area: Cancer biology
Keywords: CLL, microenvironment, CD20, BTK/PI3K inhibitors
Funding of the PhD candidate:
Part-time salary (min. 0,5 FTE) on AZV/GACR grants + doctoral scholarship + CEITEC PhD School scholarship. Guaranteed net income after taxes of min. 29.400 CZK.
Requirements for candidate:
Motivated and hard-working person with strong critical thinking skills and a willingness to learn new knowledge and techniques. A person who can work independently as well as be a team player and learn from others in the lab.
Finished master’s degree in molecular biology, biochemistry, or similar field with deep interest in molecular biology and cancer cell biology.
More information about the research group: http://mrazlab.ceitec.cz/
Start date: September 2026
Sign-up link: https://www.ceitec.eu/therapy-induced-changes-in-cd20-expression-and-microenvironmental-interactions-in-chronic-lymphocytic-leukemia/t11645
