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PhD topic / position: MICROENVIRONMENTAL INTERACTIONS IN THE BIOLOGY OF B CELL LEUKEMIAS AND LYMPHOMAS


   CEITEC

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  Prof M Mráz  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Supervisor:  Marek Mraz

Supervisor: Marek Mráz H-index 22 (citations at WOS > 1600, 46 publications with IF)

Topic 1: Regulation of cell migration in B cell leukemias and lymphomas

Annotation: The project goal is to understand the molecular machinery that regulates the migration of malignant B cells between different niches such as lymphoid and bone marrow niche and peripheral blood. This is of great interests a general mechanism of how migration is regulated in cancer cells, but also especially in chronic lymphocytic leukemia (CLL), which is a disease dependent on the B cell recirculation between different compartments (reviewed in Seda and Mraz, 2015; Seda et al, 2021). In CLL, but also in other lymphomas, the malignant B cells permanently re-circulate from peripheral blood to lymph nodes and back, and blocking this recirculation can be used therapeutically since malignant B cells depend on signals in the immune microenvironment. However, the factors that regulate this are mostly unclear. The lab established several models for in vitro and in vivo studies of microenvironmental interactions and their interplay.

We have identified candidate molecules that might act as novel regulators of the B cell migration or the balance between homing and survival in peripheral blood. This will be further investigated by the PhD student using technics such as genome editing (CRISPR), RNA sequencing, use of primary samples, functional studies with various in vitro and in vivo models. The research is also relevant for understanding resistance mechanisms to BCR inhibitors, pre-clinical development of novel drugs and their combinations (several patents submitted by the lab).

Recommended literature:

  • Seda et al….Mraz FoxO1-GAB1 Axis Regulates Homing Capacity and Tonic AKT Activity in Chronic Lymphocytic Leukemia. Blood 2021 March (epub).
  • Pavlasova G, et al…. Mraz M. Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis. Blood. 2016 Sep 22;128(12):1609-13. doi: 10.1182/blood-2016-04-709519. Epub 2016 Aug 1. PMID: 27480113 Free PMC article
  • Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol. 2015 Mar;94(3):193-205. doi: 10.1111/ejh.12427. Epub 2014 Sep 13. PMID: 25080849 Review.

Topic 2: Lymphoid microenvironment models and their use to study targeted therapy and resistance in B cell malignancies

Annotation: Chronic lymphocytic leukemia (CLL) cells and indolent lymphomas are known to be dependent on diverse microenvironmental stimuli providing them signals for survival, development, proliferation, and therapy resistance. It is known that CLL cells undergo apoptosis after cultivation in vitro, and therefore it is necessary to use models of CLL microenvironment to culture CLL cells long-term and/or to study their proliferation. Several in vitro and in vivo models meet some of the characteristics of the natural microenvironment based on coculture of malignant cells with T-lymphocytes or stromal cell lines as supportive cell, but they also have specific limitations.

The aim of this research is to develop and use models mimicking lymphoid microenvironment to study novel therapeutic options, e.g. drugs targeting CLL proliferation, development of resistance in long-term culture or combinatory approaches, which cannot be analysed in experiments based on conventional culture of CLL/lymphoma primary cells. This project will utilize models developed in the laboratory and will further optimize and modify them. Using kinase inhibitors, the biology of CLL and responses to targeted treatment will be interrogated. The student will utilize various functional assays, RNA sequencing, genome editing, drug screening etc., with the use of primary patient’s samples and cell lines.

Recommended literature:

  • Pavlasova G, et al…. Mraz M. Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis. Blood. 2016 Sep 22;128(12):1609-13. doi: 10.1182/blood-2016-04-709519. Epub 2016 Aug 1. PMID: 27480113 Free PMC article
  • Kipps et al. Chronic lymphocytic leukaemia. Nat Rev 2017 https://pubmed.ncbi.nlm.nih.gov/28102226/
  • Seda V, Mraz M. B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. Eur J Haematol. 2015 Mar;94(3):193-205. doi: 10.1111/ejh.12427. Epub 2014 Sep 13. PMID: 25080849 Review.

Topic 3: Long non-coding RNAs (lncRNAs) in the pathogenesis of B cell lymphomas

Annotation: Follicular lymphoma (FL) is a type of blood cancer that originates from B-lymphocytes, and it is the most common type of indolent non-Hodgkin lymphoma. The clinical course of FL patients can be surprisingly variable (survival from months to decades) and FL still remains incurable. The course of the disease is characterized by repeated relapses leading to the evolution of resistant disease or to the high-grade transformation to a more aggressive diffuse large B-cell lymphoma (DLBCL). This is associated with remarkably poor prognosis and a high risk of early death. Number of studies showed that multiple genetic lesions are associated with FL transformation (tFL); however, precise molecular mechanisms underlying this process is largely unclear. Importantly, the role of long non-coding RNAs in this process is completely unknown. However, we have recently described the role of short-noncoding miRNAs roles in transformed FL (Musilova et al…Mraz, Blood, 2018). The aim of the project is to reveal the molecular mechanisms involving lncRNAs and/or miRNAs responsible for FL transformation. The primary samples collected before and after high-grade transformation will be analyzed on the level of protein-coding as well as non-coding genes (NGS with Illumina, preliminary data available). This will be followed by searching for function of tFL-associated lncRNAs.

Recommended literature: 

  • Sharma et al. …Mraz. miR-29 Modulates CD40 Signaling in Chronic Lymphocytic Leukemia by Targeting TRAF4: an Axis Affected by BCR inhibitors. Blood 2020 Nov (epub). https://pubmed.ncbi.nlm.nih.gov/33171493/
  • Musilova et al. …Mraz. miR-150 downregulation contributes to the high-grade transformation of follicular lymphoma by upregulating FOXP1 levels . Blood. 2018 Nov 29;132(22):2389-2400. https://pubmed.ncbi.nlm.nih.gov/33786575/
  • Musilova K, Mraz M. MicroRNAs in B-cell lymphomas: how a complex biology gets more complex. Leukemia. 2015 May;29(5):1004-17
  • 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/

More information on CEITEC PhD School website: https://ls-phd.ceitec.cz/ and Research Group website: https://www.ceitec.eu/microenvironment-of-immune-cells/rg115

In case you are interested. ​Please, submit your CV and motivation letter via Registration Form.

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