Job Information
Organisation/Company: CEITEC MU
Research Field: Biological sciences; Chemistry » Biochemistry
Researcher Profile: First Stage Researcher (R1)
Application Deadline: 30 Sep 2026 - 21:50 (UTC)
Country: Czech Republic
Type of Contract: Temporary
Job Status: Full-time
Offer Starting Date: 1 Feb 2027
Is the job funded through the EU Research Framework Programme? Not funded by a EU programme
Is the Job related to staff position within a Research Infrastructure? No
Offer Description
Doctoral study program: Biomedical Sciences
Form of study: doctoral full time
Supervisor: Mgr. Veronika Šandová, Ph.D.
Consultant: Prof. Marek Mraz, MSc., MD, Ph.D.
Topic title: Mechanisms of Adaptation to BTK Inhibitors and Regulation of CD20 Expression in Chronic Lymphocytic Leukemia
Annotation
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and serves as a paradigm for cancers that critically depend on signals from the tumor microenvironment. Aberrant B-cell receptor (BCR) signaling and interactions within lymphoid niches provide essential survival and proliferation cues to malignant cells, making the BCR pathway one of the most successful therapeutic targets in modern hematology. Small-molecule inhibitors targeting Bruton's tyrosine kinase (BTK) and PI3Kδ have transformed the treatment landscape of CLL and other B-cell malignancies. Nevertheless, these therapies are not curative, and leukemic cells frequently adapt through alternative signaling mechanisms that allow disease persistence and progression.
This PhD project aims to uncover the molecular mechanisms by which CLL cells respond and adapt to BTK inhibitor therapy, with a particular focus on the regulation of CD20 expression and transcriptional reprogramming induced by BCR pathway inhibition. CD20 is one of the most important therapeutic targets in B-cell malignancies and forms the basis of widely used treatment strategies involving anti-CD20 monoclonal antibodies and CD20-directed CAR T-cell therapies. However, the biological regulation of CD20 expression and its modulation during targeted therapy remain incompletely understood. Previous work from our laboratory demonstrated that BTK inhibitors induce extensive changes in gene expression and significantly suppress CD20 transcription, resulting in reduced CD20 surface expression on CLL cells. These findings suggest that targeted therapies may directly influence the efficacy of combination regimens involving anti-CD20 antibodies. Understanding the molecular basis of this phenomenon is therefore of substantial clinical relevance.
The project will investigate how different BTK inhibitors affect transcriptional networks, chromatin regulation, and signaling pathways in CLL cells. A central hypothesis is that BTK inhibition alters the activity of key transcription factors that simultaneously regulate CD20 expression and promote non-genetic adaptation to therapy. The candidate will identify these regulatory mechanisms and determine how they contribute to treatment response, residual disease persistence, and therapeutic resistance. The research will combine cutting-edge experimental approaches, including CRISPR-mediated genome engineering, transcriptomic and epigenomic profiling (RNA-seq and ChIP-seq), signaling pathway interrogation, and functional studies using primary patient samples collected before and during treatment. Findings will be validated in advanced in vitro systems and relevant mouse models to establish their biological and therapeutic significance.
By elucidating how CLL cells adapt to BCR pathway inhibition, this project will provide important insights into the biology of targeted therapies and may help explain why certain BTK inhibitors perform differently in combination with anti-CD20 antibodies or venetoclax. The results are expected to identify novel mechanisms of therapeutic adaptation and resistance, potentially leading to improved treatment strategies for patients with CLL and other B-cell malignancies. The project offers comprehensive training in cancer biology, signal transduction, transcriptional regulation, functional genomics, and translational hematology. The successful candidate will work in a highly collaborative and internationally connected research environment, participate in leading national and international scientific conferences, and develop the skills required for an independent career in biomedical research.
Recommended literature
- 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/
- 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/
- 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/
- 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/
- 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, cancer immunotherapy
Keywords
CLL, microenvironment, CD20, BTK/PI3K inhibitors, BCR signaling
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
- Molecular biology enthusiast motivated to study current issues of CD20 biology and immunotherapy in CLL.
- 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.
Start date: February 2027 or sooner
Where to apply
Work Location(s)
Number of offers available: 1
Company/Institute: CEITEC MU
Country: Czech Republic
City: Brno
Postal Code: 625 00
Street: Kamenice 753/5
This is a Preview Listing…
You must sign in to see the full job description, and to apply.
Manage / Upgrade this job to a Full Job Listing.
Find Your Best Opportunity
Tell them AcademicJobs.com sent you!