Leukaemia

Question 1

What are genetic risk factors for neurodegenerative diseases?

Answer 1

• NOT usually hereditary - (except for some cases of Chronic Lymphocytic Leukaemia (CLL))
• Some rare genetic diseases may predispose to leukaemia, e.g. Fanconi’s anaemia, Down’s syndrome
• Gene mutations involving oncogenes (activation) or/and tumour suppressors (inactivation)- these genetic mutations also common to other malignancies (TP53- Li-Fraumeni syndrome, NF1-Neurofibromatosis) or specific to leukaemia and Chromosome aberrations: Translocations (e.g. BCR-ABL in CML) and Numerical disorders (e.g. trisomy 21-Down syndrome).
• Inherited immune system problems (e.g. Ataxia-telangiectasia, Wiskott-Aldrich syndrome).

Question 2

What is the prevalence of chronic myeloid/granulocytic leukaemia?

Answer 2

Chronic myeloid/ granulocytic leukaemia

• Prevalence: 742 new cases diagnosed in the UK every year (peak rate = 85-89y/o).

Question 3

What is the origin of CML?

Answer 3

• Origin: Large numbers of mature myeloid white blood cells.

Question 4

What are the symptoms of CML?

Answer 4

Symptoms: Often asymptomatic and discovered through routine blood tests.

Question 5

What is the diagnosis of CML?

Answer 5

Diagnosis: through full blood count as it will show Very high white cells count (neutrophilia) in blood and bone marrow, presence of Philadelphia chromosome (result of chromosomal translocation)

Question 6

What is the treatment of CML?

Answer 6

Treatment: Targeted therapy: Imatinib.

Question 7

What is the outcome of CML?

Answer 7

Outcome: 5-year event-free survival (EFS) of 90%. If not treated then Eventually progresses to accelerated phase and then blast crisis. For this allogeneic bone marrow transplant treatment is used

Question 8

What do 95 % of CML genes have?

What is this a result of?

Answer 8

BCR- ABL oncogene
• 95% of cases of CML have a detectable Philadelphia chromosome (Ph’)

o This chromosome is the result of balanced translocation from the long arm of chromosome 9 and the long arm of chromosome 22.

Question 9

What does the CML translocation bring together?

Answer 9

This translocation brings together two small segments of chromosome that together, form a small new chromosome that is the Philadelphia chromosome.

Question 10

What are the 2 genes affected by this translocation?

Answer 10

The two genes immediately affected by this translocation are BCR found on chromosome 22 and ABL found on chromosome 9.

Question 11

What is the BCR gene?

Answer 11

BCR is a gene that encodes a protein that is continuously active and ABL encodes tyrosine kinase who’s activity is tightly regulated (auto-inhibition).

Question 12

What does the combination of these 2 genes cause?

What is the result of this?

Answer 12

The combination of these two genes causes the promoter of BCR to start regulating ABL creating a BCR-ABL oncogene.

o The result is constitutive tyrosine kinase activity.
o This causes proliferation of progenitor cells in the absence of growth factors, decreased apoptosis, and decreased adhesion to bone marrow stroma.

Question 13

What are the applications of BCR-ABL?

How can it be detected?

What happens if both are present?

Answer 13

Applications of BCR-ABL oncogene
• Used for Diagnosis of CML- 95% of cases of CML have a detectable Ph’ chromosome.

o It can be detected through FISH with different colours for the ABL (red) and BCR (green) genes.

o In the case where both are present, the DNA will appear yellow.

Question 14

How does the detection of minimal residual disease involve?

Answer 14

Detection of minimal residual disease. A second use of the BCR-ABL oncogene is that it is used to minimal residue disease (i.e. if disease will persist after treatment).

Question 15

What is the therapy for minimal residual disease?

Answer 15

Therapy: Drugs that specifically inhibit BCR-ABL. e.g. Imatinib (Glivec®, STI571).

Question 16

What is imatinib and its role?

Answer 16

Imatinib is a small molecule inhibitor that targets ABL by binding to the ATP binding site on tyrosine kinase.
o It inhibits BCR-ABL but does not affect most other tyrosine kinases.

Question 17

What is the consequence of minimal residual disease?

Answer 17

The consequence of this is it causes apoptosis of CML cells and it induces remission in more patients with greater durability and fewer side effects.
o Some patients may become drug resistant and therefore require different therapy

Question 18

What do cases for negative for BCR-ABL require therapy wise?

What is the outcome?

Answer 18

Cases negative for BCR-ABL require different therapy
o In some cases, Imatinib is combined with chemotherapy is what is known as targeted therapy.

o This has a positive outcome in treating CML as well as in the treatment of gastrointestinal stromal tumours and SCLC (small cell lung cancer) (see right the effect of the treatment via Imatinib on tumour).

Question 19

How does imatinib exert its effects?

Answer 19

Treatment via Imatinib also appears to be dose dependant after in vitro experiments on CML cell lines.

Question 20

What is leukemia?

Answer 20

SUMMARY
• Leukaemia is a cancer of the blood cells that can be classified according to cell linage (lymphoid or myeloid) and degree of terminal differentiation (acute or chronic).

Question 21

What is acute leukemia?

Answer 21

Acute leukaemia has an earlier onset being the commonest cancer of the childhood. Evolves rapidly and requires prompt intervention with chemotherapy.

Question 22

What is chronic leukemia?

Answer 22

Chronic leukaemia is a later onset disease that generally progresses in indolent manner.

Question 23

Do therapies show promise?

Answer 23

Targeted therapies are emerging in order to treat the disease based on the genomic alterations. e.g. Imatinib to treat chronic myeloid leukaemia (CML) BCR-ABL+.