Cancer Genetics Myc over-expression – t(8;14) translocation Another paradigm: Altered regulation of tyrosine kinases

Cancer Genetics 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)

Cancer Genetics 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.

Cancer Genetics 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.

Cancer Genetics

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

Kinase activity of c-Abl required for: – Transformation (in Bcr-Abl context) – Regulation of p53

c-Abl Kinase Domain Structure

STI-571

STI-571 Patients with Ph+ CML treated with STI-571 had estimated overall survival rates of 91% in late chronic phase, 66% in accelerated phase, and 18% in blast crisis 2 years after initiating treatment.

HER2/ErbB2 and Breast Cancer

HER2/ErbB2 Therapeutics

Parametric Linkage analysis

4