The Association "Friends of Beat Leukemia Dr. Alessandro Cevenini Onlus" and the Italian Society of Experimental Hematology (SIES), thanks to the generosity of our supporters, has awarded a grant of € 30,000.00 to Francesca Arruga, young researcher of the Department of Medical Sciences and Human Genetics Foundation of the “Università Degli Studi di Torino”.
The Society of Experimental Hematology chose her as the best project, entitled "TRANSLATIONAL NOTCH1 IMPLICATIONS OF MUTATIONS IN CHRONIC lymphocytic LEUKEMIA”. This project will follow in supporting the research on the “Biomarkers syndromes chronic lymphoproliferative disorders”.
Brief project presentation written by Francesca Arruga:
"Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia in Western countries,. The clinical course is highly heterogeneous and, therefore, a “watch-and-wait” approach is often the strategy of choice, waiting for the disease to progress or become symptomatic to start treatment. Hence, the early and correct identification of patients with unfavorable prognosis is a major priority in CLL research. NOTCH1 PEST domain mutations are the most frequent somatic mutations in CLL. The prevalence at diagnosis is ~ 10-12%, increasing to 18-20% in progressive or relapsed patients and reaching 30% in patients undergoing Richter’s syndrome transformation. As shown by independent groups, NOTCH1 mutated (M) CLL patients have shorter overall survival, time to treatment and progression free survival compared to wild-type (WT) patients, indicating that NOTCH1 mutations represent an independent negative prognostic factor for the disease.
My previous work has contributed to show that in CLL i) NOTCH1 mutations have stabilizing effects on the pathway and that ii) micro-environmental interactions are critical to activate signaling, both in WT and M patients. In NOTCH1 M cells, interactions with environment selectively activates non-canonical NOTCH1 pathway, leading to increased survival and protection from drug-induced apoptosis. Both these conditions can be reverted by NOTCH1 inhibitors, thus making this pathway a potential therapeutic target.
The ultimate goal of the present project is to dissect NOTCH1 molecular pathway and to answer the question whether NOTCH1 may be a molecular target for selected CLL patients. The project hinges around three main tasks. The first investigates the crosstalk between NOTCH1 and other central pathways in CLL biology that drive disease progression likely by stimulating cell proliferation and leading to accumulation of genetic lesions. Exploring the cross-talk between NOTCH1 and other microenviroment-driven pathways may inspire novel pharmacological combinations designed to be particularly effective on the M patients. Specific attention will be dedicated to the B-Cell Receptor (BCR) pathway and to the effects induced by IgM cross-linking on NOTCH1 signaling.
The second aim addresses the role of NOTCH1 mutations in determining resistance to antibody-based therapy, as clinical observations pointed out that NOTCH1 M CLL patients are less responsive to anti-CD20-based chemoimmunotherapy. Our studies will focus on the mechanisms regulating complement- or Ab-dependent cytotoxicity, and how they are activated in response to different anti-CD20 Abs. In all instances a cohort of NOTCH1 M and WT CLL cells will be comparatively assessed exploring also the impact of NOTCH1 inhibitors.
The third goal is to generate a CLL cell line model, either NOTCH1-KO or expressing a M form, using the CRISPR-Cas9 technology. The cell lines thus generated will contribute to define the role of NOTCH1 in CLL pathogenesis and will simulate the genetic lesion found in CLL patients providing an accurate model to be used in xenograft experiments)".
www.beat-leukemia.org
Fondazione Beat Leukemia Dr Alessandro Cevenini - CF 94618790151 | Legal Notices | Realizzazione sito web: Progetto Web