Overview

Doctoral study program
Biomedical Sciences (Faculty of Medicine, Masaryk University)

Study plan
Molecular Medicine

Form of study
doctoral full time

Department
CEITEC MU and Dept of Internal Medicine, Hematology and Oncology

Supervisor
RNDr. Josef Večeřa, Ph.D.

Annotation
Transcription factors (TFs) are important regulators of cell growth, development, and hematopoietic cell differentiation. Disrupting the mechanisms that are responsible for the proper function of the transcription apparatus can lead to the onset of blood cell malignancies. The abnormal function of TFs due to dysregulation or genomic aberrations are often associated with the development of leukemias, including chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Much evidence from the latest research shows that CLL cells have an extra deregulated chromatin structure and show an increased incidence of activated enhancer and promoter areas, allowing TFs to bind and subsequently aberrantly activate potential oncogenes. Moreover, specific post-translational modification of some TFs have been noted as a result of dysregulated signaling in the leukemia microenvironment and this also contributes to disease progression. However, it remains largely unknown which TFs and how they contribute to the development and aggressiveness of CLL and other B malignancies. This project aims to describe the role of candidate TFs in the development and progression of B-cell malignancies with emphasis on CLL while also testing targeted therapy options, e.g. using specific inhibitors of TFs or chromatin modification regulators that are currently available or in development.

We have identified several TFs that might act as novel regulators of the B cell survival, proliferation and crosstalk with other immune cells. The PhD student will further investigate this using techniques such as genome editing (CRISPR), RNA sequencing, use of primary samples, and functional studies with various in vitro and in vivo mouse models. The research is also relevant for understanding resistance mechanisms to targeted therapy.

Recommended literature
Beekman et al. The reference epigenome and regulatory landscape of chronic lymphocytic leukemia. Nature Medicine 2018. https://pubmed.ncbi.nlm.nih.gov/29785028/
Sun et al. The immune microenvironment shapes transcriptional and genetic heterogeneity in chronic lymphocytic leukemia. Blood Advances 2022. https://pubmed.ncbi.nlm.nih.gov/35358998/
Hoferkova et al. Stromal cells engineered to express T cell factors induce robust CLL cell proliferation in vitro and in PDX co-transplantations allowing the identification of RAF inhibitors as anti-proliferative drugs. Leukemia 2024. https://pubmed.ncbi.nlm.nih.gov/38877102/
Research area
Cancer biology

Keywords
CLL, transcription factor, epigenetics, microenvironment

Funding of the PhD candidate
Part-time salary (min. 0,5 FTE) on AZV/GACR grants + national scholarship (equals approx. half-time salary); guaranteed net income after taxes of min. 25.000 CZK

Requirements for candidate
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.
Information about the supervisor
H-index 12, citations at WOS: 368, 17 publications in impacted journals. Former principal investigator of GACR funding. Fellowship at Karolinska Institutet (Stockholm) in research group of Dr. Emma Andersson and prof. Urban Lendahl. Supervision of diploma (4) and bachelor (11) students. 5 years of experience in the CLL and hematological malignancies field. 12 years of expertize in immunology, molecular physiology, stem cell research and mouse model developmental studies.

More information on the Marek Mráz Research Group (mrazlab.ceitec.cz).

Lab funded by prestigious grants (ERC, EHA, AZV, GAČR)

Information about the application process
https://www.ceitec.eu/ls-mm-phd/

Application webpage
https://www.ceitec.eu/role-of-transcription-factors-in-onset-and-progression-of-b-cell-malignancies/t11432