L11 - CML - from Chromosomes to Targeted Therapy Flashcards
What is chronic myeloid leukaemia (CML)?
CML is a type of myeloproliferative disease in which neutrophils are produced in excess
What is the Philadelphia chromosome?
- A chromosome produced by a reciprocal translocation between chromosomes 9 and 22
- The translocation is such that the abl gene (on chromosome 9) becomes adjacent to the bcr gene (on chromosome 22) on the Philadelphia chromosome. Together, these genes are known as the bcr-abl genes
- It is the chromosomal abnormality that underlies CML
What is the protein product of the abl gene?
What is the effect of fusing the bcr and abl genes?
- Abl is a tyrosine kinase that phosphorylates ADP to stimulate cell proliferation
- The effect of fusing bcr and abl is constitutive expression of the bcr-abl protein
List 3 effects of the bcr-abl protein.
The bcr-abl protein causes:
1 - Increased proliferation
2 - Decreased apoptosis
3 - DIsturbance of the interaction with the cell’s extracellular matrix
*This is similar to the function of abl - the bcr-abl protein is a kinase for ADP. The function of bcr is not understood
How might a patient with CML present?
- The presentation is variable and often asymptomatic
1 - Small haematocrit
2 - Leukostasis (elevated blast cell count and decreased tissue perfusion due to high blood viscosity)
3 - Tiredness
4 - Anaemia (of other blood cells) due to an increase in production of neutrophils
5 - High white blood count
6 - Splenomegaly
7 - Hepatomegaly
8 - Infection due to impaired function of white blood cells
9 - Abnormal platelet count
10 - Gout
11 - Priapism
Why can CML cause gout?
- Gout is a form of arthritis that forms due to a buildup of uric acid crystals
- Uric acid is a breakdown product of DNA, which is present in higher concentrations in CML due to the elevated neutrophil count
List the conditions seen on blood count and other biochemical investigations that indicate CML.
What might give similar results to CML that has to be excluded before making a diagnosis?
1 - Elevated white cell count
2 - Low Hb
3 - Possible impaired liver function
4 - Possible impaired renal function (due to increased uric acid)
5 - Raised lactate dehydrogenase
6 - Philadelphia chromosome present
- Infection will give similar results - need to exclude
Why is identifying the Philadelphia chromosome on a karyotype insufficient to confirm CML?
How can CML be confirmed by further investigating the Philadelphia chromosome?
- There are many forms of the Philadelphia chromosome due to the different loci at which the bcr-abl genes can be fused
- Not all forms of the Philadelphia chromosome cause CML
- PCR can be done to confirm the presence of the specific form of the Philadelphia chromosome that causes CML (only a specific template sequence will work in PCR)
List 5 acute treatments for CML.
What is the purpose of each treatment?
1 - Hydroxyurea (prevents cell cycle continuation)
2 - Leukapheresis (to reduce white blood count. It involves removing blood, centrifuging it to remove the WBCs and returning the blood to the patient)
3 - Allopurinol (to treat potential gout)
4 - IV fluids (to prevent renal failure)
5 - Analgesia (to relieve pain)
List 3 chronic treatments for CML.
1 - Tyrosine kinase inhibitors
2 - Interferons
3 - Allogeneic stem cell transplant
List 5 tyrosine kinase inhibitors.
1 - Imatinib
2 - Dasatinib
3 - Nilotinib
4 - Bosutinib
5 - Ponatinib
What is the mechanism of action of tyrosine kinase inhibitors for treatment of CML?
- TKI binds ATP binding pocket of BCR-ABL protein
- Inhibits binding of ATP to ABL kinase to prevent phosphorylation of target molecules
- BCR-ABL remains inactive so no downstream signalling or cell proliferation
