Ph.D Thesis


Ph.D StudentBesser Elazar
SubjectAntitumoral Effects of Phytocannabinoids in Notch 1
Mutated T-cell Acute Lymphoblastic
Leukemia
DepartmentDepartment of Biology
Supervisor DR. David Meiri


Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a type of blood cancer that accounts for approximately 10-20% of all acute lymphoblastic leukemias. Most T-ALL-affected individuals harbor genetic mutations or deletions in several onco- and tumor-suppressor genes including Notch1. The most frequent T-ALL Notch1 mutations are in the heterodimerization (HD) and polypeptide enriched in proline, glutamate, serine and threonine (PEST) domains. Mutations of the HD domain allow a ligand-independent activation of the NICD promoting the uncontrolled growth of T-ALL cells. In this work I have identified a specific Cannabis extract that inhibits cellular proliferation and induces apoptosis in leukemia cells, by preventing Notch1 maturation and leading to downregulation of the Notch1 intracellular domain (NICD). I further identified and isolated the three specific phytocannabinoids that are responsible for reducing cells viability, increasing apoptosis, reducing NICD formation, and reducing tumor size and weight in-vivo. This is the first work to identify the specific combination of compounds, which confer the anti-tumor effect of the whole Cannabis plant extract. I show their mechanism of action and identify NOTCH1 as a new molecular target for phytocannabinoids. These results may pave the way for the establishment of a new pharmacotherapy for the treatment of NOTCH1 mutated cancers such as T-ALL.