Assignment information

Question 1

What is RARa’s role in health?

Answer 1

RARa is a gene. It makes a protein called RARa.

On its own, RARa doesn’t allow transcription of genes that allow for growth and differentiation of white blood cells.

HOWEVER,
When retinoic acid binds with RARa, it enables transcription of genes involved in growth and differentiation for white blood cells.

Question 2

What is PML’s role in health?

Answer 2

PML is a gene that produces the PML protein.

1. It is a tumour suppressor: it stops cells from replicating too quickly
2. It forms PML nuclear bodies which have a role in blocking proliferation (of abnormal cells) and inducing apoptosis

Question 3

How does PML/RARa cause APL?

Answer 3

The unnatural fusion of the PML and RARa gene produces a PML/RARA protein that results in the effects of APL.

PML/RARA causes proteins to be recruited that STOP transcription of growth genes. Therefore, this means that the cells cannot differentiate, and you have the build up immature cells.

In addition, PML nuclear bodies can’t be made so the blocking or proliferation and apoptosis for these “abnormal cells” cannot take place.

It’s like driving a car into a wall.

Question 4

What are the three phases of APL treatment? Explain these phases.

Answer 4

There are three phases of treatment:

1. Induction:
Goal: Reduce number of leukaemic cells
Drugs used: 
* ATRA with an anthracycline (chemotherapy) 
* ATO 

ATRA plus ATO is often the preferred treatment in people at lower risk of the leukemia coming back, as it tends to have fewer side effects. Chemo is more likely to be included in treatment if this risk is higher

2. Consolidation:
Goal: Keep the patient in remission 
Drugs used are either: 
* ATRA with ATO 
* ATRA with anthracycline 
* ATO with anthracycline
Duration: several months until no new leukaemic cells are seen

3. Maintenance:
   For high- risk relapse patients, consolidation is followed. Lower doses of the drugs are used for a longer period of time.
   Drugs used: ATO alone or ATO with an anthracycline

Question 5

What type of chemotherapy is used for APL?

Answer 5

Anthracyclines

Question 6

Describe how anthracyclines work

Answer 6

• They are extracted from Streptomyces bacterium
• They work by inhibiting topoisomerase II activity (a molecule that manages tangled DNA so replication can occur)
• It inserts itself into DNA and prevents it from unwinding

Question 7

Name the anthracycline used to treat APL

Answer 7

Daunorubicin and

Idarubicin

Question 8

How does ATO treat APL?

Answer 8

• ATO binds to the PML portion of the PML-RARα protein
• This causes oxidation of the protein, eventually leading to its degradation
• Thus, all blood cells possessing leukemic abnormalities will eventually be removed.

Question 9

How does ATRA treat APL?

Answer 9

• ATRA binds to the RARα segment in the PML-RARα protein

* This allows the RARα protein to regain its normal function of enabling RAR-mediated promyelocyte differentiation.

Question 10

What is the position of the PML gene on the chromosome?

Answer 10

It is located on the long q arm of chromosome 15 at position 24. 1

Question 11

What is the position of the RARa gene on the chromosome?

Answer 11

It is located on the long q arm of chromosome 17 at position 21. 2

Question 12

What is karyotyping?

Answer 12

Karyotyping is the process of taking a picture of someone’s chromosomes.

The chromosomes are isolated, stained, and examined under the microscope.
Most often, this is done using the chromosomes in the white blood cells.

Question 13

What are side effects of ATO?

Answer 13

• Fatigue
• Fever
• Vomiting
• Belly pain
• Diarrhoea
• Neuropathy
• Changes in heart rhythm

Question 14

What are side effects of ATRA?

Answer 14

• Fatigue
• Fever
• Vomiting
• Bone pain
• Rash
• Headache
• Dry skin
• Eye irritation
• Mouth sores

Question 15

What type of mutation mediates APL?

Answer 15

It is a somatic mutation (mutations that occur in all cells of the body. except germ cells).

Somatic mutations are NOT inheritable.