1. Notch1 and its role in pre-T-cell acute lymphoblastic leukemia (T-ALL)
Erin Campbell

2. Notch Background
Thomas Hunt Morgan discovered Notch pathway in Drosophila melanogaster
One of the big five pathways in development
Regulates cell proliferation, survival, positioning, and differentiation

3. Structure of Notch1 Notch1 encodes a transmembrane receptor protein
Extracellular domain has EGF-like repeats and intracellular domain has PEST domain

4. Notch1 Signaling Pathway

5. Notch1 regulates thymocyte specification
Grabher et al. Nature Reviews. 2006

6. Inhibition of Notch1 suppressed growth in T-ALL cells
Weng et al. Molecular and Cellular Biology 2003.

7. Pre-T-cell acute lymphoblastic leukaemia (T-ALL)
1,500 people in US affected per year
80% survival rate in children, 30-40% in patients under 60, and 10% in patients over 60
Accounts for % of pediatric and 25% of adult ALL cases

8. Chromosomal Translocation in T-ALL results in overexpression of Notch1
This translocation was the first discovery of Notch1 and its role in T-ALL
Rare translocation that only occurs in 1% of cases

9. Somatic Mutations in Notch1
Heterodimerization (HD) Mutation
PEST mutation

10. The Big Picture about Notch1
Notch1 encodes a transmembrane receptor protein
One specific function of Notch1 is the regulation the specification and development of T-cells
In T-ALL, Notch1 is overexpressed leading to deregulated proliferation of thymocytes and the formation of tumors