Pathophysiology of CML

Pathophysiology of CML

· Due to growth and replication of an abnormal clone

· Philadelphia chromosome
o 9-22 reciprocal translocation
§ ABL – 9
§ BCR - 22
o BCR-ABL gene fusion
§ ABL – tyrosine kinase
§ BCR – break cluster region (normal function unknown)
§ Leads to disregulated tyrosine kinase activity (ABL)
o BCR-ABL fusion protein expressed
§ Increased activity
§ Causes the leukaemia
§ Normally, ABL acts in the nucleus - inhibits the retinoblastoma gene à inhibits cell growth
§ In CML, ABL acts mainly in the cytoplasm à constitutive tyrosine kinase activity – cellular transformation and deregulated growth (inhibition of apoptosis)

· Initially - Expansion of semi-mature granulocytes (Myeloid stem cell line)
o production of immature cells
· Acquisition of additional genetic mutations
o ‘blastic crisis’
o Can cause acute myeloid or acute lymphatic leukaemia