Makindo Medical Notes

First discovered at the University of Pennsylvania in Philadelphia by Peter Nowell in 1960, the Philadelphia chromosome is a key finding in Chronic Myeloid Leukaemia (CML) and some cases of Acute Lymphoblastic Leukaemia (ALL). CML was the first cancer to be directly linked to a clear genetic abnormality—the 9;22 translocation.

About the Philadelphia Chromosome and CML

• Chromosomal Translocation: Each human cell contains 23 pairs of chromosomes. In most cases of CML, a "swapping" or translocation of DNA occurs between chromosomes 9 and 22 during cell division. Part of chromosome 9 is transferred to chromosome 22, and vice versa. This results in a shortened chromosome 22, known as the Philadelphia chromosome.
• Formation of the BCR-ABL Fusion Gene: The ABL gene from chromosome 9 fuses with the BCR (Breakpoint Cluster Region) gene on chromosome 22. This fusion gene produces a protein of either p210 or p185 molecular weight. The ABL portion of this fusion gene carries a domain with tyrosine kinase activity, which is critical for the abnormal cell signalling pathways leading to unchecked bone marrow proliferation in CML.
• BCR-ABL Protein: The swapping of DNA forms a new gene (an oncogene) called BCR-ABL, which produces the BCR-ABL protein. This protein, a type of tyrosine kinase, drives the uncontrolled growth and reproduction of CML cells. However, drugs such as imatinib can inhibit the tyrosine kinase activity of this protein, thereby controlling the progression of leukaemia.
• Key Abbreviations: BCR refers to the "breakpoint cluster region" gene from chromosome 22, while ABL refers to the "Abelson tyrosine kinase" gene from chromosome 9. The fusion of these genes creates a constitutively active tyrosine kinase protein, driving cancerous cell growth.

Role of Tyrosine Kinases in Cell Biology

• Signalling Cascade: Tyrosine kinases are essential mediators in cellular signalling cascades. They play crucial roles in various biological processes in response to internal and external stimuli.
• Functions: Tyrosine kinases help regulate:
  • Cell growth
  • Cell differentiation
  • Cell metabolism
  • Cell apoptosis (programmed cell death)
• Enzymatic Activity: Tyrosine kinases are a family of enzymes that catalyse the phosphorylation of specific tyrosine residues in target proteins using ATP. This phosphorylation is key to activating or deactivating various cell functions.
• Mutations Leading to Cancer: While tyrosine kinase activity is tightly regulated in normal cells, mutations (such as the 9;22 translocation) can transform them into oncogenes, leading to malignancy.
• Impact of Imatinib (Gleevec): Although the 9;22 translocation still occurs in CML, imatinib (Gleevec) effectively inhibits the BCR-ABL protein’s tyrosine kinase activity. By blocking the ability to phosphorylate proteins, the drug halts cell proliferation and survival signals, effectively controlling the disease.