Project description DEENESFRITPL The role of microenvironmental interactions in chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the western world. A critical component in CLL pathogenesis is the activation of the B-cell receptor signalling taking place in lymph nodes, and in the context of other microenvironmental interactions (such as CLL-T cell interaction). The EU-funded LeukemiaEnviron project is investigating how CLL cells behave in the microenvironment of immune niches. This includes analysis of CLL samples at various times during the disease course, during microenvironment-targeting therapies, and comparison of CLL cells in lymph nodes and peripheral blood. Results may have important clinical ramifications, and researchers also aim to develop a novel mouse model of the disease. Show the project objective Hide the project objective Objective B cell chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults. CLL cells are characterized by their universal dependency on pro-survival and pro-proliferative signals from immune niches. To achieve this they constantly re-circulate between blood and lymph nodes, which is inhibited by novel microenvironment-targeting therapies such as “BCR inhibitors”. We aim to reveal how the malignant B cells change the propensity of their signalling pathways in response to the different microenvironments such as peripheral blood vs lymph node to obtain the proliferative signals. This is of major relevance for CLL, but also transferable to the biology of some other B cell malignancies and/or normal B cells. We analyzed the “finger print” of microenvironmental interactions in many CLL samples at various times during the disease course or during therapy. The obtained data led us to hypothesize on the mechanisms of regulation of signalling propensity of two pathways that are responsible for proliferation and survival of CLL cells, namely B Cell Receptor (BCR) signalling and signals from T-cells mediated by CD40/IL4. In aim 1 we hypothesize that CD20 is one of the key proteins involved in CLL cell activation, and influences BCR and interleukin signalling (see figure). This has important therapeutic implication since CD20 is used as a therapeutic target for 20 years (rituximab), but its function in CLL/normal B cells is unknown. In aim 2 we hypothesize that miR-29 acts a key regulator of T-cell signalling from CD40 and down-stream NFkB activation (see figure). This represents the first example of miRNAs‘ role in the propensity of T-cell interaction, and could be also utilized therapeutically. In aim 3 we will integrate our data on microenvironmental signaling (aim 1+2) and develop a first mouse model for PDX that would allow stable engraftment of primary CLL cells. Currently, CLL is non-transplantable to any animal model which complicates studies of its biology. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesclinical medicineoncologyleukemia Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2018-STG - ERC Starting Grant Call for proposal ERC-2018-STG See other projects for this call Funding Scheme ERC-STG - Starting Grant Host institution Masarykova univerzita Net EU contribution € 1 499 990,00 Address Zerotinovo namesti 9 601 77 Brno Czechia See on map Region Česko Jihovýchod Jihomoravský kraj Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 499 990,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all Masarykova univerzita Czechia Net EU contribution € 1 499 990,00 Address Zerotinovo namesti 9 601 77 Brno See on map Region Česko Jihovýchod Jihomoravský kraj Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 499 990,00
