Haem: Acute Leukaemia Pt.1

Question 1

Which cell level does CML mutations tend to occur in?

Answer 1

Pluripotent haematopoietic stem cell

Question 2

Which cell level does AML tend to occur in?

Answer 2

Pluripotent haematopoietic stem cell or multipotent myeloid stem cell

Question 3

List some types of chromosomal abnormalities that can occur

Answer 3

• Duplications
• Loss
• Translocation
• Inversion
• Deletion

Question 4

How can altered DNA sequence lead to leukaemia?

Answer 4

• By the creation of a fusion gene (AML and ALL)
• By abnormal regulation of genes (mainly ALL)

Question 5

Which chromosomal duplications are most commonly associated with AML?

Answer 5

chr 8 and chr 21 (hence the predisposition seen in Down syndrome)
Duplication means extra copies of proto-oncogenes

Question 6

How might chromosomal deletion be oncogenic in AML

Answer 6

Loss of tumour suppressor genes or DNA repair genes
(common in AML, specifically deletions in chr 5 and chr 7)

Question 7

List some molecular abnormalities that an occur in apparently normal chromosomes.

Answer 7

• Point mutations
• Loss of function of tumour suppressor genes
• Partial duplication
• Cryptic deletion (formation of a fusion gene by deletion of a small section of DNA)

Question 8

Describe the epidemiology of AML

Answer 8

Incidence increases with age

Question 9

Describe the basic pathogenesis of AML

Answer 9

Block in the maturation of granulocytes leads to abnormal proliferation of blast cells

Question 10

List some risk factors for AML.

Answer 10

• Familial
• Constitutional (e.g. Down syndrome)
• Anti-cancer drugs
• Irradiation
• Smoking

Question 11

What are type 1 and type 2 abnormalities with regards to leukaemogenesis?

Answer 11

• Type 1: promote proliferation and survival (anti-apoptosis)
• Type 2: block differentation (this would normally be followed by apoptosis)

NOTE: leukaemogenesis in AML requires multiple genetic hits i.e. a type 2 abnormality alone would not be enough to cause leukaemia

Question 12

What is the main role of transcription factors?

Answer 12

• They bind to DNA, alter the structure to favour transcription and, ultimately, regulate gene expression
• Disruption of transcription factors can result in failure of differentiation

Question 13

Give an example of how disruption of a transcription factor can lead to leukaemogenesis.

Answer 13

• Core binding factor (CBF) is the master controller of haemopoiesis
• Translocation 8;21 fuses RUNX1 with CBF leading to the formation of a fusion gene that drives leukaemia
• The fusion transcription factor binds to co-repressors leading to a differentiation block
• Inversion of chromosome 16 also affects CBF in a similar way

Question 14

Which chromosomal aberration causes APML?

(Acute Promyelocytic leukaemia)

Answer 14

Translocation 15;17

Question 15

What is a complication of APML? Why does this occur?

Answer 15

• Haemorrhage - this is because APML is associated with DIC and hyperactive fibrinolysis

Question 16

Name the fusion gene that is responsible for APML.

Answer 16

PML-RARA

Question 17

What is the difference in the maturity of cells in AML vs APML?

Answer 17

Block in maturation occurs later in the granulocyte lineage in APML, hence the proliferation of promyelocytes

Question 18

Which microscopic feature is pathognomonic of myeloid leukemias?

Answer 18

Auer rods

Question 19

In what way are the promyelocytes in APML considered ‘abnormal’ histologically?

Answer 19

They contain multiple Auer rods

Question 20

Describe how the variant version of APML is different from the original version.

Answer 20

• The variant form has granules that are below the resolution of a light microscope
• They also tend to have bilobed nuclei

Question 21

Give a type 1 and type 2 mutation for APML.

Answer 21

• Type 1: FLT3-ITD
• Type 2: PML-RARA

Question 22

Give a type 1 and type 2 mutation for CBF leukaemias.

Answer 22

• Type 1: sometimes mutated KIT
• Type 2: mutations affecting function of CBF

Question 23

Which stain can be used to distinguish myeloid leukaemias from other leukaemias?

Answer 23

Myeloperoxidase

Question 24

List the clinical features of AML.

Answer 24

Systemic symptoms - Bone marrow failure:

• Anaemia - pallor, fatigue
• Neutropaenia - infection
• Thrombocytopaenia - bleeding

Local infiltration:

• Splenomegaly
• Hepatomegaly
• Gum infiltration (if monocytic)
• Lymphadenopathy (occasionally)
• CNS, skin or other sites

DIC

Hyperviscosity (if WCC is very high) - retinal haemorrhages and exudates