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
Prof. Marek Mraz, MSc., M.D., Ph.D.

Annotation
Marek Mraz research group has a long-term interest in non-coding RNAs and microenvironmental interactions of malignant B cells, and this research has been supported by an ERC Starting grant (2019-2024). We have previously described novel regulators of microenvironmental interactions including short non-coding RNAs, microRNAs (Sharma et al…Mraz, Blood, 2021; Musilova et al…Mraz, Blood, 2018; Cerna et al…Mraz, Leukemia, 2019). MicroRNAs were shown to play a pivotal role in B cell functions; however, the functions of long non-coding RNAs (lncRNAs) remain unclear. We aim to decipher for the first time the role of lncRNAs in B cell receptor (BCR) signaling and B-T cell interactions. Human genome contains large numbers of lncRNAs that can regulate various physiological cellular processes or contribute to the onset or aggressiveness of cancer. We will study lncRNAs in the context of chronic lymphocytic leukemia (CLL), which is driven by aberrations in the BCR pathway and B-T interactions. Regulation of BCR pathway and B-T cell interactions by lncRNAs is likely of relevance for CLL, but is also transferable to the biology of other B cell malignancies, autoimmune diseases and normal B cells. We identified 3 candidate lncRNAs involved in microenvironmental interactions of CLL. We will decipher the molecular functions of these lncRNAs using biochemical and cellular approaches and via a novel lncRNA knock-out mouse model. We have engineered mice for genetic loss of one of these lncRNAs, and the student will analyse the phenotype of these mice and breed them with known CLL mouse models (Eu-TCL1). Detailed biochemical/molecular studies will complement these data and we will also analyze primary samples from patients with B cell malignancies. We will identify functions of lncRNAs using CRISPR interference, RNA pulldown experiments, mouse models, and molecular biology technics. Furthermore, we developed a novel co-culture model inducing robust primary CLL cell proliferation (~50%) in vitro (Hoferkova et al, Leukemia, 2024). We aim to utilize this game-changing tool to perform the first-ever CRISPR screening of lncRNAs/genes regulating primary CLL cell proliferation. This will help better understand the disease biology and possibly identify novel molecular targets for therapy.

Recommended literature
Zeni and Mraz LncRNAs in adaptive immunity: role in physiological and pathological conditions. RNA Biol. 2021 May;18(5):619-632. https://pubmed.ncbi.nlm.nih.gov/33094664z
Mattick JS, et al. Long non-coding RNAs: definitions, functions, challenges and recommendations. Nat Rev Mol Cell Biol. 2023 Jun. https://pubmed.ncbi.nlm.nih.gov/36596869/
Sharma et al. …Mraz. miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors. Blood 2021. https://pubmed.ncbi.nlm.nih.gov/33171493/
Musilova K, Mraz M. MicroRNAs in B-cell lymphomas: how a complex biology gets more complex. Leukemia. 2015 May;29(5):1004-17
Research area
Cancer biology

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

Requirements on candidates
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.
Keywords
lymphoma, CLL, lncRNA, microenvironment

Information about the supervisor
H-index 30 (citations > 3500, 50 publications with IF), currently principal investigator of 4 grants (AZV 3x, NPO, in the past ERC Starting grant). Dr. Mraz has currently 7 PhD students, with 3 finishing soon). international collaborations: University of Southampton, Univ.California- San Diego, Mayo Clinic, Dana-Farber Cancer Institute, EMBL, University of Turin (student internship available), member of EHA Comittee, reviewer in scientific journals: Blood, Leukemia, Leukemia Research; https://is.muni.cz/auth/osoba/101627;

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

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

Application webpage
https://www.ceitec.eu/long-non-coding-rnas-lncrnas-in-microenvironmental-interactions-of-b-cell-chronic-lymphocytic-leukemia/t11430