B-cell acute lymphoblastic leukaemia-derived large oncosomes; where they go and what they do

• Applicant: Dr. Valentina René Minciacchi
• Subject Area: Hematology, Oncology ; Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 449828949

Within the bone marrow microenvironment (BMM) the different cell types collaborate in order to maintain the homeostasis of the organ and contribute to the regulation of the fate of the normal haematopoietic stem cells (HSC). In pathological condition, leukeamia cells take advantage of this complex structure to obtain support for their growth and protection from the effect of drugs. This is the result of a continuous exchange of information between the leukaemia cells and the BMM in which leukaemia cells educate the BMM toward the establishment of a permissive environment and therefore the cells in the BMM sustain leukaemia progression. These interactions have been slowly elucidated and recent efforts have been aimed to identify strategies to target the mediators of the reciprocal conditioning between leukaemia and the BMM which might be useful assets to existing therapies. Extracellular vesicles (EVs) are closed entities that are released by cells and mediate the transfer of complex information to target cells in the form of proteins, lipids and nucleic acids. EVs have been recently implicated in intercellular communication in several tumor types including leukaemia. Our preliminary data show that, in vivo, leukaemia cells shed large oncosomes (LO), a specific population of EVs that so far has been reported to be released mainly by tumor cells and contribute to tumor growth. We focused our attention on precursor B-cell acute lymphoblastic leukaemia (B-ALL) which seems to shed large amounts of LO. B-ALL is one of the most common paediatric cancer and is characterized by the enhanced proliferation of cells of the lymphoid lineage. B-ALL derived LO promote the education of the BM stromal cells toward the acquisition of a tumor supportive phenotype. Hypothesizing that B-ALL derived LO have a key role in the intercellular communication in leukaemia, in the current proposal we aim to investigate:1. The LO shedding rate variation during leukaemia progression.2. The mechanism by which B-ALL derived LO affect stromal cells phenotype.3. The possible strategies to block the exchange of LO and delay the progression of the disease. This will be carried out with the support of a transplantation-based murine model of leukaemia or xenotransplantation experiments using human samples, various in vitro assays, multiphoton and confocal microscopy, as well as high throughput omics analysis and biochemical studies performed with the help of our collaborators. These results will have high impact on the understanding of the complex interactions between leukaemia and the BMM and will provide useful insight for the development of adjunct therapy to existing treatment strategies for B-ALL.

• DFG Programme: Research Grants