Flashcards in Topic F4 Deck (7):
What is the major cause of chromosomal rearrangements?
- Double stranded DNA breaks that are repaired incorrectly resulting in chromosomal translocations
What types of cancers are chromosomal translocations most often detected in?
- Haematological malignancies; leukemia and lymphoma
e.g. the oncogenes causing CML and B cell lymphomas are associated with chromosomal translocations
What are the two types of Leukemia and how do they differ?
- Acute: high level mutations in very undifferentiated white blood cells leading to a short life expectancy
- Chronic: slower proliferation of more differentiated cells leading to a longer life expectancy
How do chromosomal translocations cause Leukemia?
-Part of one chromosome attatching to another part of a different chromosome causes the formation of fusion genes which can code for fusion proteins at the break points on each chromosome.
- Chromosomal translocations can cause leukemia by two methods: activation of an oncogene, inactivation of a tumour suppressor gene.
What chromosomal translocation causes chronic myeloid leukemia?
- Recipricol translocation of Abl tyrosine kinase from chromosome 9 to BCR (break point cluster region) on chromosome 22
- This creates a characteristic shortened chromosome 22 called the Philedelphia chromosome which encodes a BCR-Abl tyrosine kinase fusion protein which has increased tyrosine kinase activity as it is no longer being inhibited and there is constitutive Abl tyrosine kinase activity leading to increased cell growth and inhibition of cell death
How does Gleevac treat CML?
- Gleevac inhibits the activity of Abl-tyrosine kinase and thus prevents Abl tyrosine kinase constitutive activity causing uncontrolled cell growth