Philadelphia chromosome

First discovered at the University of Pennsylvania in Philadelphia by Peter Nowell in 1960 and can be seen in CML and some ALL. CML is the 1st cancer to be linked to a clear genetic abnormality - the 9;22 translocation

About

• Each human cell contains 23 pairs of chromosomes. Most cases of CML start when a "swapping/translocation" of DNA occurs between chromosomes 9 and 22 during cell division. Part of chromosome 9 goes to 22 and part of 22 goes to 9. This gives rise to a chromosome 22 that is shorter than normal known as the Philadelphia chromosome.
• The ABL gene on chromosome 9 is fused to the BCR (Breakpoint Cluster Region) gene on chromosome 22 The fusion gene generates a protein of p210 or p185 weight. ABL carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase) Therefore: The BCR/ABL1 fusion gene product is a tyrosine kinase. Tyrosine kinase activity is responsible for the activation of signal transduction pathways which leads to abnormal bone marrow proliferation
• The swapping of DNA between the chromosomes leads to the formation of a new gene (an oncogene) called BCR-ABL. This gene then produces the BCR-ABL protein, which is the type of protein called a tyrosine kinase. This protein causes CML cells to grow and reproduce out of control. The action of the Tyrosine kinase can be inhibited by drugs such as imatinib. This can control leukaemia.
• Abbreviations: BCR (breakpoint cluster region) gene from chromosome 22 to the ABL (Abelson tyrosine kinase) gene from chromosome 9 ultimately results in a constitutively active tyrosine kinase protein.

Tyrosine Kinases

• Tyrosine kinases are important mediators of the signalling cascade. Tyrosine kinases play key roles in diverse biological processes in response to external and internal stimuli
• Tyrosine kinases help control Cell growth, Cell differentiation, Cell metabolism, Cell apoptosis (cell death)
• Tyrosine kinases are a family of enzymes which catalyze the phosphorylation of select tyrosine residues in target proteins using ATP
• Though their activity is tightly regulated in normal cells, they may acquire transforming functions due to mutations, which may lead to malignancy
• Although the 9;22 translocation still occurs, the imatinib (Gleevec) locks it up so it is unable to receive the phosphate resulting in a blocked signal for cell proliferation & survival