Finding Cancer Genes

CML: Chronic Myelogenous Leukemia – Asymptomatic at time of diagnosis Abnormal white blood cell count Stable for 3 – 5 years followed by “Blast Crisis” Fatal within 3 – 6 months of Blast crisis 20% of all leukemia's 5000 cases per year in US (compare with 180,000 lung cancer cases)

Finding Cancer Genes CML: Chronic Myelogenous Leukemia – All CML cells harbor Philadelphia chromosome 1960: Peter Nowell David Hungerford Nowell P, Hungerford D. "A minute chromosome in chronic granulocytic leukemia." Science 1960;132:1497.

Finding Cancer Genes 1973: Janet D. Rowley Discovered t(9;22) Rowley JD. "A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining [letter]". Nature 1973;243:290–3.

Finding Cancer Genes

Bcr-Abl

Non-physiological Activation of Bcr-Abl Activation of Signaling

c-Abl – Physiological Roles c-Abl is a nuclear-shuttling protein that regulates p53

c-Abl – Physiological Roles

c-Abl Kinase Domain Structure

STI-571

Parametric Linkage analysis

3

Fig. 1. The β-catenin protein interaction network. Michael B. Major et al. Science 2007;316: Published by AAAS

Fig. 3. WTX promotes β-catenin ubiquitination and degradation. Michael B. Major et al. Science 2007;316: Published by AAAS

Tumour Suppressors Example 4: REST

Thomas F. Westbrook, Eric S. Martin, Michael R. Schlabach, Yumei Leng, Anthony C. Liang, Bin Feng, Jean J.... A Genetic Screen for Candidate Tumor Suppressors Identifies REST Cell, Volume 121, Issue 6, 2005,