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The impact of the tissue microenvironment on the microRNAs in chronic lymphocytic leukemia

Final Report Summary - VIMIRNASCLL (The impact of the tissue microenvironment on the microRNAs in chronic lymphocytic leukemia)

The VimiRNAsCLL ( microRNA and CLL) stems from the main issue of the chronic lymphocytic leukemia (CLL): the management of patients with progressive disease. CLL is the most diffuse leukemia in the Western world. The majority of CLLs are diagnosed in an indolent phase and run an indolent course for a long period of time without requiring therapy; however about 30–40% of patients progress to a more advanced clinical stage and ultimately die from the disease. Therefore, one of the major challenges is to identify and characterize key progression genes. The European project aims at identifying phenomena that differentially affect microRNAs already shown deregulated over CLL progression. Special interest was given to the microenvironment, since all relevant events of CLL occur in tissues where leukemic cells can be exposed to antigen stimulation and microenvironment can influence the cell's destiny.

In the field of microenvironment the research has made progress in understanding that T lymphocytes if activate by specific antibodies involved in the immune response, promote the transcription of the miR-181b in B cells. However in B cells of lymph nodes from CLL patients, where the cross-talk between B and T cells should be active, the miR-181b is very low and bordered in cellular compartments where it cannot act on anti-apoptotic targets. This could explain how the cells' fate could change: the leukemic cell survives rather than die. Moreover, the leukemic cell exploits the loss of miR-181b to escape the cytotoxic activity of T cells. Indeed miR-181b decreases inhibitory signals for the maturation of cytotoxic T lymphocytes in such a way as to facilitate leukemic cell death.

On the other hand, VimiRNAsCLL add insight in the genetics complexity of CLL and experimental work has led to demonstrate double allele-specific transcriptional regulation of miR-15a/16-1 by alternative mechanisms that could affect in different ways cell cycle and apoptosis. CLL cells in most of the case randomly lose one of this allele, thereby only one mechanism is dominant. Being the two alternative regulations specifically associated with a CLL prognostic factor, differential usage of these two mechanisms may distinguish at onset aggressive from indolent forms of CLL, providing the basis for the clinical heterogeneity of a subset of CLL patients.

The research can contribute to the development of new cancer therapies that use microRNAs, generating considerable benefits to the management of CLL patients whose disease will eventually progress. This will also serve to stimulate the industry to generate advanced technology for the delivery of new drugs.
In parallel, one of the major successes of the European research VimiRNAsCLL has also been its contribute to develop an independent laboratory with complete scientific autonomy which trained 2 Post doctoral fellowship, 2 PhD students, 2 fellowships, 4 undergraduate students and one apprentice. Several volunteer s also joined the laboratory to be trained in cancer research field. Among the post doctoral fellow one is currently in the lab and the other one is employee in a different laboratory of the University of Chieti. Among the PhD students the graduated one is now working in the lab as Post doctoral research. About the fellowship one is currently in the lab and the other one is working in a different field of research in France. Among the undergraduate students two are now graduated and employed at the Hospital of Chieti and at a pharmaceutical industry in London (UK).

Exchanges between collaborators' team members were done, allowing people to broaden their field of competences and to enforce collaborations. Five international meetings gave the opportunity to present widely the work performed in VimiRNAsCLL.