Doctoral study program: Biomedical Sciences

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.

Topic title: ROLE OF TRANSCRIPTION FACTORS IN ONSET AND PROGRESSION OF B-CELL MALIGNANCIES

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 + doctoral scholarship + CEITEC PhD School scholarship. Guaranteed net income after taxes of min. 29.400 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.

Start date: September 2026

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