Chronic Myeloid Leukaemia: From Chromosomes to Targeted Therapy Flashcards
To which group of diseases does chronic myeloid leukaemia (CML) belong?
CML is a type of myeloproliferative disease.
Which cell is affected in chronic myeloid leukaemia?
How are they affected?
- Neutrophils are affected in CML.
- They 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?
Abl is a tyrosine kinase that phosphorylates ADP to stimulate cell proliferation.
What is the effect of fusing the bcr and abl genes?
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.
Describe the presentation of a patient with chronic myeloid leukaemia.
- 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 (the only cure!).
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?
- The tyrosine kinase inhibitors inhibit the bcr-abl protein.
- This prevents phosphorylation of ADP by BCR-ABL, which in turn inhibits downstream signalling for proliferation.
- This causes cell death.
Give an example of a mechanism by which resistance to imatinib can come about.
How is a patient that is resistant to imatinib treated for CML?
- Imatinib resistance can come about if the bcr-abl gene mutates.
- If this occurs, there are 4 other tyrosine kinase inhibitors available (see previous card for list) that tend to work.
- A particular mutation of bcr-abl known as T315I causes resistance to all of the drugs except for ponatinib.
- The probability of mutation if only using one agent is relatively high.
