Forensics

BCR-ABL

• Philadelphia chromosome - Karyotyping
• BCR-ABL fusion protein - FISH
• 9 to 22 chromosomal translocation
• c-ABL is tyrosine kinase, BCR-ABL makes it constituitively active no longer under GF control
• Causes Chronic Myeloid Leukaemia (In mature myeloid cells)
• Excess proliferation of cells due to BCR2 inhibiting apoptosis, JAK/STAT/ and Ras/MAPK induce proliferation
• Can progress to Acute Myeloid Leukaemia (In blast cells) and very resistant to Imatinib at this stage as ^ BCR-ABL
• Resistance due to different point mutations in BCR-ABL gene- evolving cancer?
• Imatinib: Nicholas Lydon, late 1990s based on phenylaminopyrimidine (added methyl and benzamide), Dasatinib is second generation drug.