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Advanced Nano and Microtechnologies Advanced Materials Structural Biology Gen. and Prot. of Plant Systems Molecular Medicine Brain and Mind Research Molecular Vet. Medicine

Marek Mráz Research Group

Research Group Leader
Researcher ID
Phone: +420 54949 8143
E-mail:
Office:
Web: www.ceitec.cz/mrazlab/
Address: Office: Kamenice 753/5, Brno, 625 00 (BUILDING A35, OFFICE 216)

Research areas

  • The role of microRNAs/lncRNAs in BCR-signalling and adhesion in B cell malignancies (Chronic Lymphocytic Leukemia, B-Cell Lymphomas)
  • The role of non-coding RNAs in DNA damage response in B cell malignancies (Chronic Lymphocytic Leukemia, B-Cell Lymphomas)
  • Development of novel targeted therapies in B cell malignancies (miR-therapy, targeting of BCR-signalling/adhesion)
  • Prognostic and predictive markers in hematological malignancies

Main objectives

We study the molecular pathways that regulate microenvironmental interactions in normal and malignant immune cells. The microenvironment of immune niches plays an important role in the onset, progression, and resistance of hematological malignancies. We largely focus on the role of non-coding RNAs (microRNAs [miRNAs] and long-noncoding RNAs [lncRNA]) in these pathways. The deregulation of non-coding RNAs can lead to aberrant regulation of pathways that are canonically associated with cancer biology like apoptosis, proliferation and differentiation. However, the role of non-coding RNAs in the microenvironmental interactions of normal and malignant cells is largely unknown.

Content of research

The biology of malignancies derived from „mature“ B cells is largely driven by two molecular pathways that are crucial for the biology of B cells (i) deregulation of B cell receptor signalling, (ii) microenvironment interactions in lymph nodes and bone marrow (reviewed in Seda and Mraz, EJH, 2014)1. These events are interconnected since the normal and malignant B cells are stimulated by antigens and antigen-presenting cells in the context of their microenvironment. Activation of both pathways leads to up-regulation of numerous anti-apoptotic/pro-proliferative molecules and cell adhesion leads to enhanced receptiveness to BCR-signalling and vice versa.  It has been shown that these pathways are both important in the onset, progression and resistance of B cell malignancies like chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), and mantel cell lymphoma. Targeting microenvironmental interactions in immune niches is currently one of the most promising therapeutic approaches and an important part of the mechanism of action of BCR-inhibitors like ibrutinib or idelalisib (FIG. 1).  However, the mechanisms for BCR (de)regulation and mechanism of action of BCR-inhibitors are largely unknown (reviewed in Seda and Mraz, EJH, 2014). Similarly, the role of miRNAs in the regulation of the complex BCR signalling cascade remains one of the highly interesting, yet poorly explored questions, in the biology of normal and malignant B cells.

Mraz1

FIG. 1. The crosstalk of BCR signalling and adhesion/migration in B cells, and their therapeutic targeting (Seda and Mraz, EJH, 2014)1


We study molecular pathways involved in microenvironmental interactions in B cell malignancies, and specifically focus on those whose targeting could potentially mimic or synergize with BCR-inhibitors. We mainly focus on “indolent” B cell malignancies (CLL and FL), where there is an unmet clinical need to identify patients with aggressive disease (especially a subset of ~20% of FL patients with unfavorable prognosis) that can benefit from novel and expensive therapeutic approaches, and to describe predictors of response to BCR-inhibitors. We have shown that microRNAs (miRNAs) play a key role in the regulation of microenvironmental interactions, and their expression can be used as prognostic/predictive biomarkers or therapeutically exploited.The discovery of non-coding RNAs, particularly miRNAs, changed the understanding of the biology of normal and malignant B cell and regulation of cell physiology in general. MicroRNAs constitute about 5% of predicted genes in the genome and a single miRNA regulates, based on an incomplete complementarity, many mRNAs which has important consequences for gene regulation. Identifying miRNA targets is not easy since a large number of genes can be influenced by miRNA levels and this is context dependent. MicroRNAs can act as a simple negative regulation of a target mRNA, but it seems that a common scenario is their participation in positive/negative feedback/feed-forward regulatory loops (see Musilova and Mraz, Leukemia, 2015) (FIG. 2). Chronic lymphocytic leukemia (CLL) serves as a prototype malignancy to study the role of miRNAs since it was also the very first human disease associated with deregulation of miRNA expression 8. Several studies including ours have identified ~25 miRNAs differentially expressed between indolent versus aggressive disease (reviewed in Mraz et al., 2009, 2013), including their contribution to p53-pathway deregulation in CLL (Mraz et al., Leukemia, 2009, Mraz et al., Blood, 2012, Mraz et al., Leuk Lymph, 2009). Importantly, we have shown for the first time that miRNAs, namely miR-150, can regulate BCR signalling by directly affecting GAB1 and FOXP1 levels in malignant and normal B cells (Mraz et al., Blood, 2014). We have also shown that miRNAs can target the negative regulators of BCR signalling like SHIP-1 phosphatase (Cui et al., Blood, 2014).

We aim to further describe the role of non-coding RNAs and their targets in the regulation of microenvironmental interactions like adhesion and BCR signalling, and to use this therapeutically.

 

mráz3

Fig. 2. The contribution of altered miRNA expression to the molecular pathogenesis of B-cell lymphomas. The first row represents the upstream regulation of miRNAs, followed by the primary (third row) and secondary (fourth row) miRNA targets. The last row shows the overall impact of miRNA deregulation on the B-NHL biology (Musilova and Mraz, Leukemia, 2015).


 

list / cards

Name and position

E-mail

Phone

Marek Mráz, M.D., PhD
Research Group Leader
+420 54949 8143
Gabriela Pavlasová
+420 54949 8144
Václav Šeda
+420 54949 8144
Kateřina Černá
Researcher
+420 54949 8144
Jan Oppelt
PhD Student
+420 54949 8144
Kateřina Henzlová
Student
+420 54949 8144
Veronika Krmeská
Student
+420 54949 8144
Sonali Sharma
Lenka Humpolíková Adámková, Ph.D.
+420 54949 3878
Kateřina Musilová
Researcher
+420 54949 8144

SELECTED PUBLICATIONS

2017

  • PAVLASOVA, G; BORSKY, M; SVOBODOVA, V; MUSILOVA, K; CERNA, K; SEDA, V; OSICKOVA, J; BRYCHTOVA, Y; DOUBEK, M; POSPISILOVA, S; MAYER, J; MRAZ, M, 2017:BCR SIGNALLING PROFICIENT CHRONIC LYMPHOCYTIC LEUKAEMIA B CELLS ARE PRONE TO RITUXIMAB MEDIATED ELIMINATION IN VIVO. HAEMATOLOGICA 102 , p. 412 - 412.

2016

  • PAVLASOVA, G; BORSKY, M; SEDA, V; CERNA, K; OSICKOVA, J; DOUBEK, M; MAYER, J; CALOGERO, R; POSPISILOVA, S; DAVIDS, M; BROWN, J; MRAZ, M, 2016:IBRUTINIB INHIBITS CD20 UP-REGULATION ON CLL B CELLS MEDIATED BY THE CXCR4/SDF-1 AXIS. HAEMATOLOGICA 101 , p. 47 - 47.
  • PAVLASOVA, G; BORSKY, M; SEDA, V; CERNA, K; OSICKOVA, J; DOUBEK, M; MAYER, J; CALOGERO, R; TRBUSEK, M; POSPISILOVA, S; DAVIDS, MS; KIPPS, TJ; BROWN, JR; MRAZ, M, 2016:Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis. BLOOD 128 (12), p. 1609 - 1613.

2015

  • DOLEZALOVA D; MRAZ M; HAMPL A, 2015:miRNA in Embryonic Stem Cells. In MICRORNA IN REGENERATIVE MEDICINE (book chapter)
  • MALCIKOVA, J; STANO-KOZUBIK, K; TICHY, B; KANTOROVA, B; PAVLOVA, S; TOM, N; RADOVA, L; SMARDOVA, J; PARDY, F; DOUBEK, M; BRYCHTOVA, Y; MRAZ, M; PLEVOVA, K; DIVISKOVA, E; OLTOVA, A; MAYER, J; POSPISILOVA, S; TRBUSEK, M, 2015:Detailed analysis of therapy-driven clonal evolution of TP53 mutations in chronic lymphocytic leukemia. LEUKEMIA 29 (4), p. 877 - 885.
  • MUSILOVA, K; MRAZ, M, 2015:MicroRNAs in B-cell lymphomas: how a complex biology gets more complex. LEUKEMIA 29 (5), p. 1004 - 1017.
  • PAVLASOVA, G; SEDA, V; BORSKY, M; CERNA, K; OSICKOVA, J; MAYER, J; POSPISILOVA, S; DAVIDS, MS; BROWN, JR; MRAZ, M, 2015:Microenvironmental Interactions up-Regulate CD20 Expression in CLL B Cells through the CXCR4/SDF-1 Axis: Implications for CD20-Targeting Antibodies and the Use of BCR-Inhibitors in Combination. BLOOD 126 (23)
  • SEDA, V; MRAZ, M, 2015:B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells. EUROPEAN JOURNAL OF HAEMATOLOGY 94 (3), p. 193 - 205.
  • TOM, N; MALCIKOVA, J; RADOVA, L; KANTOROVA, B; PARDY, F; PAVLOVA, S; PAL, K; MRAZ, M; TICHY, B; DOUBEK, M; BRYCHTOVA, Y; PLEVOVA, K; MAYER, J; TRBUSEK, M; POSPISILOVA, S, 2015:MUTATIONS IN THE TP53 GENE SHOW FEATURES OF SOMATIC HYPERMUTATION PROCESS WITH PROMINENT DIFFERENCE BETWEEN IGHV MUTATED AND UNMUTATED CHRONIC LYMPHOCYTIC LEUKEMIA. HAEMATOLOGICA 100 , p. 224 - 225.

2014

  • CUI, B; CHEN, LG; ZHANG, SP; MRAZ, M; FECTEAU, JF; YU, J; GHIA, EM; ZHANG, L; BAO, L; RASSENTI, LZ; MESSER, K; CALIN, GA; CROCE, CM; KIPPS, TJ, 2014:MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia. BLOOD 124 (4), p. 546 - 554.
  • MRAZ, M; CHEN, LG; RASSENTI, LZ; GHIA, EM; LI, HY; JEPSEN, K; SMITH, EN; MESSER, K; FRAZER, KA; KIPPS, TJ, 2014:miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1. BLOOD 124 (1), p. 84 - 95.

2013

  • MRAZ, M; KIPPS, TJ, 2013:MicroRNAs and B cell receptor signaling in chronic lymphocytic leukemia. LEUKEMIA & LYMPHOMA 54 (8), p. 1836 - 1839.

2012

  • DOLEZALOVA, D; MRAZ, M; BARTA, T; PLEVOVA, K; VINARSKY, V; HOLUBCOVA, Z; JAROS, J; DVORAK, P; POSPISILOVA, S; HAMPL, A, 2012:MicroRNAs Regulate p21(Waf1/Cip1) Protein Expression and the DNA Damage Response in Human Embryonic Stem Cells. STEM CELLS 30 (7), p. 1362 - 1372.
  • MRAZ, M; DOLEZALOVA, D; PLEVOVA, K; KOZUBIK, KS; MAYEROVA, V; CERNA, K; MUSILOVA, K; TICHY, B; PAVLOVA, S; BORSKY, M; VERNER, J; DOUBEK, M; BRYCHTOVA, Y; TRBUSEK, M; HAMPL, A; MAYER, J; POSPISILOVA, S, 2012:MicroRNA-650 expression is influenced by immunoglobulin gene rearrangement and affects the biology of chronic lymphocytic leukemia. BLOOD 119 (9), p. 2110 - 2113.
  • MRAZ, M; POSPISILOVA, S, 2012:MicroRNAs in chronic lymphocytic leukemia: from causality to associations and back. EXPERT REVIEW OF HEMATOLOGY 5 (6), p. 579 - 581.

2011

  • MRAZ, M; ZENT, CS; CHURCH, AK; JELINEK, DF; WU, XS; POSPISILOVA, S; ANSELL, SM; NOVAK, AJ; KAY, NE; WITZIG, TE; NOWAKOWSKI, GS, 2011:Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin alpha-4-beta-1 (VLA-4) with natalizumab can overcome this resistance. BRITISH JOURNAL OF HAEMATOLOGY 155 (1), p. 53 - 64.
  • TRBUSEK, M; SMARDOVA, J; MALCIKOVA, J; SEBEJOVA, L; DOBES, P; SVITAKOVA, M; VRANOVA, V; MRAZ, M; FRANCOVA, HS; DOUBEK, M; BRYCHTOVA, Y; KUGLIK, P; POSPISILOVA, S; MAYER, J, 2011:Missense Mutations Located in Structural p53 DNA-Binding Motifs Are Associated With Extremely Poor Survival in Chronic Lymphocytic Leukemia. JOURNAL OF CLINICAL ONCOLOGY 29 (19), p. 2703 - 2708.
  • VARGOVA, K; CURIK, N; BURDA, P; BASOVA, P; KULVAIT, V; POSPISIL, V; SAVVULIDI, F; KOKAVEC, J; NECAS, E; BERKOVA, A; OBRTLIKOVA, P; KARBAN, J; MRAZ, M; POSPISILOVA, S; MAYER, J; TRNENY, M; ZAVADIL, J; STOPKA, T, 2011:MYB transcriptionally regulates the miR-155 host gene in chronic lymphocytic leukemia. BLOOD 117 (14), p. 3816 - 3825.

2009

  • MRAZ, M., MALINOVA, K., KOTASKOVA, J., PAVLOVA, S., TICHY, B., MALCIKOVA, J., STANO-KOZUBIK, K., SMARDOVA, J., BRYCHTOVA, Y., DOUBEK, M., TRBUSEK, M., MAYER, J., POSPISILOVA, S., 2009:miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities. Leukemia 23 (6), p. 1159 - 1163.

1. BCR Signalling Pathway and its Crosstalk with Adhesion in the Biology of B-Cell Malignancies

Supervisor: doc. MUDr. Mgr. Marek Mráz, Ph.D.

Annotation:

The objective of the laboratory is to study the biology of hematological malignancies with a focus on pathways that regulate microenvironmental interactions of immune cells’. This is of great therapeutic interest in B cell leukemia and B cell lymphomas since inhibitors of such interactions have a promising clinical effect (such as BCR inhibitors ibrutinib and idelalisib). We have recently performed studies which revealed that the regulation of BCR signalling is dependent on adhesion and chemokine signalling, and BCR inhibitors affect these pathways dramatically (Pavlasova et al…..Mraz, Blood, 2016). We noted that B cell adhesion and chemokine signalling up-regulates several positive regulators of BCR signalling, such as adaptor molecules, and co-receptors. This allows the B cell (both normal and malignant) to change the propensity of BCR signalling in different body compartments (such as peripheral blood, lymph nodes, and bone marrow). The precise mechanisms of these regulations are largely unknown. The PhD candidate will study the molecular organization of BCR signalling and its crosstalk with cell adhesion and other microenvironmental interactions. This will be performed on primary samples from patients with B cell chronic lymphocytic leukemia, and on B cell lines. This will help to explain the basic regulations of this pathway as well as potential novel therapeutic candidates in B cell malignancies. Overall, the understanding of microenvironmental interactions is of great interest since it drives the discovery of combinatorial therapy. The project will involve various technics of molecular and cell biology such as co-culture of B cell with stromal cells from immune niches (or use of scaffold biomaterials), migration and adhesion assays, flow cytometry, western blotting, gene expression studies (Real-Time PCR and RNAseq Illumina), and modulation of pathway activity with siRNA, and small molecular inhibitors. Genome editing technics (Crispr/Cas9) will be used to functionally validate the phenotypes in B cells. To apply please contact the supervisor and submit a CV by email to: marek.mraz@email.cz.

2. Non-Coding RNAS and Microenvironmental Interactions of B-Cell Leukemias and Lymphomas

Supervisor: doc. MUDr. Mgr. Marek Mráz, Ph.D.

Annotation:

The objective of the laboratory is to study the biology of hematological malignancies with a focus on molecular pathways that regulate malignant immune cells’ microenvironmental interactions. It is now understood that pathways like the B-cell receptor (BCR) signaling are deregulated during the onset of most B cell leukemias and lymphomas. The BCR pathway is considered the most promising target for therapy in B cell malignancies. For numerous pathological processes the principal deregulation takes place at the level of such non-coding RNAs in B cell malignancies (Mraz et al., Leukemia, 2009; Mraz et al., Blood, 2012; Musilova and Mraz, Leukemia, 2015). We have recently performed studies which revealed that microRNAs regulate the B-cell receptor signaling which represents the essential pathway for the fate of normal and malignant B cells (Mraz et al., Blood, 2014; Mraz and Kipps, 2013). However, the role of non-coding RNAs in microenvironmental interactions of immune cells is largely unclear. The PhD candidate will perform integrated analysis of coding and non-coding RNAs in the regulation of fundamental microenvironmental interactions of B cell, namely adhesion and BCR signalling. The project will focus on short non-coding RNAs (microRNA) and identification of their targets, but also on long-noncoding RNAs. This will be performed using NGS technics (Illumina) in collaboration with the Genomics Core Facility of CEITEC MU, and experts in NGS data analysis (Uni Torino, CEITEC, EMBL). The candidate will use our in vitro models for microenvironmental interactions, and artificial activation/inhibition of BCR signalling to decipher the regulatory loops that involve coding and non-coding RNAs in primary leukemia cells and in lymphoma cell lines. He will utilize genome editing technics in B cells (using the Crispr/Cas9 technology) to delete miRNAs and test their effect on BCR signalling, activation of kinases and transcription factors. Project will also utilize co-culture of malignant B cells with stromal cells, and/or scaffold materials that mimic human bone marrow, and various other technics of molecular and cell biology (western blotting, cell transfection with miRNA mimics, siRNAs, flow cytometry, cloning etc). Overall, the understanding of microenvironmental interactions is of great interest since it drives the discovery of combinatorial therapy. We will further use the knowledge of gene expression networks to reveal molecular inhibitors that should be used clinically. The interactions within the immune niches are the basis for relapse, persisting minimal residual disease, failure of the immune system to target cancer cells, cell resistance to therapy and, in principle, the incurability of many hematological malignancies.
To apply please contact the supervisor and submit a CV by email to: marek.mraz@email.cz.

 

The NON-CODING AND CODING RNA NETWORKS in the MICROENVIRONMENTAL INTERACTIONS of B-CELL LEUKEMIAS AND LYMPHOMAS

PROJECT:
The objective of the laboratory is to study the biology of hematological malignancies with a focus on molecular pathways that regulate malignant immune cells’ microenvironmental interactions.  It is now understood that pathways like the B-cell receptor (BCR) signaling are deregulated during the onset of most B cell leukemias and lymphomas. The BCR pathway is considered the most promising target for therapy in B cell malignancies. For numerous pathological processes the principal deregulation takes place at the level of such non-coding RNAs in B cell malignancies (Mraz et al., Leukemia, 2009; Mraz et al., Blood, 2012; Musilova and Mraz, Leukemia, 2015). We have recently performed studies which revealed that microRNAs regulate the B-cell receptor signaling which represents the essential pathway for the fate of normal and malignant B cells (Mraz et al., Blood, 2014; Mraz and Kipps, Leuk Lymph 2013). However, the role of non-coding RNAs in microenvironmental interactions of immune cells is largely unclear.

The post-doctoral fellow will perform integrated analysis of coding and non-coding RNAs in the regulation of fundamental microenvironmental interactions of B cell, namely adhesion and BCR signalling. The project will focus on short non-coding RNAs (microRNAs) and identification of their targets, but also on long-noncoding RNAs. This will be performed using NGS technics (Illumina) in collaboration with the Genomics Core Facility of CEITEC MU, and experts in NGS data analysis (Uni Torino, CEITEC, EMBL). The candidate will use our in vitro models for microenvironmental interactions, and artificial activation/inhibition of BCR signalling to decipher the regulatory loops that involve coding and non-coding RNAs in primary leukemia cells and in lymphoma cell lines. This will also utilize co-culture of malignant B cells with stromal cells, and/or scaffold materials that mimic human bone marrow. Overall, the understanding of microenvironmental interactions is of great interest since it drives the discovery of combinatorial therapy. We will further use the knowledge of gene expression networks to reveal molecular inhibitors that should be used clinically. The interactions within the immune niches are the basis for relapse, persisting minimal residual disease, failure of the immune system to target cancer cells, cell resistance to therapy and, in principle, the incurability of many hematological malignancies.

HOW TO APPLY:
Candidates should have a PhD or MD with experience in cancer biology or molecular biology (cell culture, cloning technics, WB, flow cytometry), and should possess the ability to conduct independent research. Our institute provides outstanding laboratory facilities (including NGS) and a highly supportive environment. The successful applicant will work in a team of young investigators and will also have the opportunity to supervise doctoral/diploma students. The research will be conducted at CEITEC MASARYK UNIVERSITY (ceitec.eu) in close collaboration with Dept. of Int. Medicine, Hematology and Oncology (University Hospital Brno).

To apply, please submit a CV, a brief statement of research interests, reprints of publications by email to:  marek.mraz@email.cz

OTHER INFORMATION:

The mission of the institute is to advance the understanding of the underlying molecular and cellular mechanisms of hematological malignancies. Our laboratory is located University Campus (Kamenice 5, 4kms outside the city center). The campus provides a vibrant, multidisciplinary and highly collaborative scientific environment. The lab is located in Brno, the second-largest city in Czech Rep. that hosts 6 major universities with the biggest concentration of biomedical research in this European region. Brno is one of the major cultural hubs, with a vibrant and lively atmosphere housing ~60000 students. The city has a very good public transport and plenty of interesting places to visit within the reach of trains.
Located in the heart of Europe, Brno is within small distance of several major cities (Prague, Vienna, Bratislava, Budapest) and close to international airports (Prague, Vienna).

 

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