i) The role of microRNAs in BCR-signalling and adhesion in B cell malignancies (Chronic Lymphocytic Leukemia, B-Cell Lymphomas)
ii) The regulation of BCR signalling in B cells, and the function of CD20
iii) Development of novel targeted therapies (miR-therapy, targeting of BCR-signalling/adhesion)
iv) The role of non-coding RNAs in DNA damage response in B cells
v) Prognostic and predictive markers in hematological malignancies
i-ii) 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 (Musilova et al, Blood, 2018; Mraz et al, Blood, 2014; Musilova and Mraz, Leukemia, 2015). We also study the regulation and function of a cell-surface molecule CD20, since this molecule is used as a therapeutic target for over 20 years (Pavlasova et al, Blood, 2018; Pavlasova et al, Leukemia, 2016), but its biology is largely unknown.
iii) DEVELOPMENT OF NOVEL TARGETED THERAPIES AND BIOMARKERS (miR-therapy, targeting of BCR-signalling/adhesion). The approval of drugs that target the B cell receptor pathway (BCR) was a milestone in the therapy of B cell malignancies. However, the use of these drugs does not lead to a cure and patients relapse. We aim to a) describe the molecular pathways affected by BCR inhibition and understand mechanisms that leukemic cells use to survive, and b) to define and test “druggable” therapeutic targets that should be therapeutically combined with BTK/PI3K inhibition (Pavlasova et al, Blood, 2016). This project also includes the studies of prognostic and predictive markers in hematological malignancies.
iv-v) THE ROLE OF NON-CODING RNAS IN DNA DAMAGE RESPONSE IN B CELL MALIGNANCIES (Chronic Lymphocytic Leukemia [CLL], B-Cell Lymphomas). We have for the first time established a link between DNA damage response and the regulation of B cell receptor signalling in B cells (Cerna et al, Leukemia, 2018). We are also working on various other aspects of non-coding RNAs in DNA damage response, including their use as biomarkers (2 patents).
We study the molecular pathways that regulate microenvironmental interactions in normal and malignant immune cells. 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 onset and progression like apoptosis, proliferation and differentiation. However, the role of non-coding RNAs in the microenvironmental interactions and immune cell activation is largely unknown.
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). 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. 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.
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.
Our data demonstrate 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).
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.
ERC : European Research Council
GACR : Grant agency of the Czech Rep.
AZV MZ CR : grant agency of the Ministry of Health of the Czech Republic
EHA : European Hematology Association
GAMU : Grant Agency of Masaryk University
JCMM/JMK : South Moravian Region