Share
RNA Regulatory Networks in Aggressiveness of B Cells
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). In this project, we aim to understand how RNA regulatory networks drive the aggressiveness and transformation of follicular lymphoma (FL). Follicular lymphoma is the most common “indolent lymphoma”, but about 20% of patients have in fact an aggressive disease and/or experience a histological transformation into a highly aggressive lymphoma (diffuse large B cells lymphoma). The factors that drive aggressiveness or histological transformation remain poorly understood. The transformation has been associated with genetic alterations (such as mutations in TP53, MYC), epigenetic changes, and interactions within the tumor microenvironment that promote resistance to therapy and aggressiveness. Identifying biomarkers that predict transformation and understanding the interplay between genetic/transcriptional changes and microenvironmental factors are key to improving prognosis and treatment strategies.
We aim to decipher for the first time the role of non-coding RNAs (ncRNAs), both lncRNAs and microRNAs, as regulators of FL aggressiveness and transformation. In the past we have discovered several miRNAs that affect the biology of lymphoma B cells, but the role of lncRNAs remains completely unknown and the role of miRNAs is only partially understood (Musilova et al…Mraz, Blood, 2018; Sharma et al…Mraz, Blood, 2021; Cerna et al…Mraz, Leukemia, 2019). We have performed long and short RNA sequencing from paired samples of FL and transformed FL and from FL samples before and after relapse. This pointed to several candidate non-coding RNAs that will be further studied. We will also integrate this with identifying transcription factors responsible for differences in ncRNA expression. We will decipher the molecular functions of the ncRNAs using biochemical and cellular approaches and analyze primary samples from patients. We will identify functions of ncRNAs using CRISPR interference, RNA pulldown experiments, RNA profiling, mouse models, and molecular biology techniques. This will help better understand the disease biology and possibly identify novel molecular targets.
Recommended literature
- Devan J, Janikova A, Mraz M. New concepts in follicular lymphoma biology: From BCL2 to epigenetic regulators and non-coding RNAs. Semin Oncol. 2018 Oct;45(5-6):291-30. https://pubmed.ncbi.nlm.nih.gov/30360879/
- 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/33094664
- 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/