Leukaemia is a cancer of the white blood cells. CML tends to be hereditary.
As this is a chronic disease it is not usually diagnosed until there is:
Splenomegaly,
High white cell count,
Fatigue,
Weight loss,
Sweating,
Anaemia,
Haemorrhage,
Gout,
Retinal haemorrhage
and fever.
Looking at the bone marrow aspirates and trephines you see myeloid hyperplasia and megakaryocytes.
This often occurs as a tanslocation between chromosomes 9 and 22 (BCR-Abl) which is also referred to as the Philadelphia chromosome. There's a fusion protein which causes the Abl gene encoding for tyrosine kinase activity to become activated. This fusion protein is responsible for the CML phenotype. The Bcr-Abl gene has a kinase demain. ATP binds the BCR-Abl and a substrate is phophorylated by the ATP. The substrate is often the beginning of the Ras-Raf-Mek-Mapk signalling pathway. This activates the cell growth and proliferation.
This pathway now has a cure as Imatinib can bind into the same site that the ATP binds into, so no phosphorylation occurs and the Ras pathway is blocked. This is a targetted therapy for this disease.
Unfortunately, imatinib is not curative. However, Human stem cell transplant is. The T cells are destroyed from the person's body, and a new set is infused. This should cure the CML. Imatinib has a few problems; drug resistance and no irradication of stem cell populations. Around 14% of patients are resistant to imatinib. The cells that are reactive to imatinib are eradicated and then the cells left are not affected by the therapy. Mutations in tyrosine kinase mean resistance develops to imatinib.