Acute lymphoblastic leukemia (ALL), the most common form of malignancies in children, is induced by the transformation of blood (hematopoietic) stem cells and progenitors. The damaged cells produced in the bone marrow crowd out normal cells and also metastasize to other organs. Although the outcome of ALL patients has improved in recent years, significant numbers of patients die from recurrent disease. Better understanding of the molecular basis of this disease and the search for fresh ideas, and new-targeted therapies are thus in high gear. Recent studies have demonstrated that approximately 60% of cases of pediatric T-cell ALL (T- ALL) are marked with aberrant activation of the Notch1 receptor. However, small molecule ?-secretase inhibitors (GSIs), which abrogate oncogenic Notch1 signaling in T-ALL, fail to show objective clinical responses and cause severe toxicity. Therefore, successful targeting of Notch1 in T-ALL demands a considerable refinement of our understanding of Notch1 regulation in T cell leukemia. By using Drosophila as a genetic model, our recent study showed that UVRAG (UV irradiation resistance-associated gene), a highly conserved tumor suppressor, mediates the endocytic degradation of Notch1 and prevents its aberrant activation and cell overgrowth. Additionally, lymphocytes from UVRAG-deficient patient exhibit strongly increased Notch1 activity resulting from an impaired endocytic degradation of Notch1. These observations suggest that Notch1 represents a key target molecule of UVRAG. Given the oncogenic addiction of T-ALL to Notch1, we hypothesize that UVRAG-mediated downregulation of Notch1 plays a critical role in the development and GSIs-resistance of T-ALL. To test this hypothesis, Aim 1 will investigate the molecular mechanism by which UVRAG modulates Notch1 activation and signaling.
Aim 2 will investigate the biological significance of UVRAG-mediated downregulation of Notch1 in T cell leukemogenesis by using both cell-based assays and T-ALL xenograft mouse model. With well-established in vitro and in vivo experimental conditions, the proposed study will not only identify UVRAG as a novel and critical player in Notch1-induced T-ALL, but will also illuminate new views on Notch1 regulation for the design of more effective treatment options for patients with leukemia/lymphoma.
Aberrant Notch1 activation accounts for the majority of T-cell acute lymphoblastic leukemia (T- ALL), an aggressive malignancy induced by the transformation of blood stem cells and progenitors. The goal of this study is to investigate the molecular mechanism of the UVRAG-mediated downregulation of Notch1 in the pathogenesis and drug resistance of T-ALL. Results obtained from this study will identify UVRAG as a key element in Notch1-induced T-ALL and aid in providing novel therapeutic strategies for T-ALL patients.
