Notch1 and its role in pre-T-cell acute lymphoblastic leukemia (T-ALL)

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

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 http://www.nature.com/nri/journal/v8/n5/fig_tab/nri2304_F2.html

Structure of Notch1 Notch1 encodes a transmembrane receptor protein Extracellular domain has EGF-like repeats and intracellular domain has PEST domain http://dev.biologists.org/cgi/content-nw/full/133/17/3277/FIG1

Notch1 Signaling Pathway http://www.nature.com/nri/journal/v8/n5/fig_tab/nri2304_F2.html

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

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

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 10- 15% of pediatric and 25% of adult ALL cases http://www.cancer.gov/cancertopics/pdq/treatment/childALL/patient

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 http://www.licr.org/C_news/newslink/0406/images/0406_Notch1_Fig1.jpg

Somatic Mutations in Notch1 Heterodimerization (HD) Mutation PEST mutation http://www.nature.com/nri/journal/v8/n5/fig_tab/nri2304_F2.html

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