Leukaemia

Question 1

Compare the type of mutation in AML vs CML

Answer 1

AML - TF mutation results in dominant negative effect

CML - translocation mutation

Question 2

What is the dominant negative effect and which condition is this seen in?

Answer 2

When the product of an oncogene masks the activity of the normal homologue protein - AML

Question 3

Compare what is affected in the cell due to the mutations in AML vs CML

Answer 3

AML - cell behaviour affected

CML - signalling between surface receptors and nucleus is affected (external signalling)

Question 4

Compare the blood films of AML vs CML

Answer 4

AML - all cells look the same as they’re all immature myeloblasts
CML - variation in maturity of myeloblasts

Question 5

Compare end cell production in AML vs CML

Answer 5

AML - reduced end cell production because the cells never mature
CML - increased end cell production because the BM is pumping out loads of mature cells

Question 6

State the general signs and symptoms of leukaemia and for some signs, state which tests are done to diagnose

Answer 6

Bone pain (BM aspiration)
Hepatosplenomegaly (LFTs)
Thymic enlargement (chest x-ray)
Skin infiltration 
Leucocytosis

Question 7

State the general metabolic effects of leukaemia and the tests done to diagnose

Answer 7

High metabolic rate leads to:
-Sweating 
-Weight loss
DNA breakdown leads to: 
-Hyperuricaemia - uric acid levels
-Renal failure (uric acid deposition) - kidney function tests
Low grade fever (neutropenia)

Question 8

State specific features of AML

Answer 8

AML gives rise to monocyte-like cells which normally fight off infections, therefore you get:
- Gum swelling (deposition of monocyte-like cells near bacteria rich areas)
- Gum haemorrhage
Patient has thrombocytopenia due to BM overcrowding and DIC therefore:
- Intravascular haemorrhage

Question 9

Which type of leukaemia is most common in children? State the risk factors.

Answer 9

ALL 
Irradiation in utero 
Chemical exposure in utero
EBV infection 
Mutagenic drugs (rare)

Question 10

State some protective factors against ALL

Answer 10

Overcrowding (low socio-economic background
Large families
Early social interactions e.g. play school

Question 11

State specific features of ALL and investigations

Answer 11

Bone pain
Hepatosplenomegaly
Lymphadenopathy
Thymus enlargement
Testicular enlargement
Fatigue/lethargy/pallor/breathlessness (anaemia)
Fever/other features of infection (neutropenia)
Bruising/petechiae/bleeding (thrombocytopenia)

Question 12

State the haematological features of ALL

Answer 12

Normochromic, normocytic anaemia 
Neutropenia
Thombocytopenia 
Replacement of normal BM cells by lymphoblasts
Lymphoblasts in blood
Leucocytosis

Question 13

State the investigations for ALL and the associated symptoms/signs/reasons

Answer 13

Chest xray - thymus enlargement
LFTs - hepatomegaly
Kidney function tests - uric acid deposition
Uric acid levels - hyperuricaemia due to DNA breakdown
BM aspirate - bone pain
Blood film - check maturity/immaturity and clonal status
Blood count - anaemia, thrombocytopenia, neutropenia
Cytogenic/molecular analysis (FISH) - prognosis & research
Immunophenotyping - classify cell type

Question 14

How could you work out the prognosis for ALL?

Answer 14

Do cytogenetic/molecular analysis

Question 15

What is a marker of good prognosis in ALL?

Answer 15

Hyperdiploidy

Question 16

What is a marker of bad prognosis in ALL? Give an example

Answer 16

Translocation/fusion genes e.g. 4;11 translocation

Question 17

What are the three leukaemogenic mechanisms which have been discovered from cytogenetic analysis?

Answer 17

Fusion gene formation
Promotor gene translocation near protooncogene
Protooncogene point mutation

Question 18

Give an example of a fusion gene resulting in ALL and how this can be detected

Answer 18

ETV6-RUNX1 t(12;21)

FISH detection

Question 19

Give an example of a translocation causing ALL

Answer 19

TCL3 gene is dysregulated by proximity to TCRA gene

t(10;14)

Question 20

What are the three types of treatment for ALL and why?

Answer 20

Supportive (rbc, platelets, antibiotics) - due to anaemia, thrombocytopenia and neutropenia)
Systemic chemo
Intrathecal chemo (to get to brain)

Question 21

Name a translocation mutation causing CML

Answer 21

BCR-ABL gene

Question 22

Which conditions are risk factors for developing leukaemia?

Answer 22

Down’s syndrome
Chromosomal fragility syndromes
DNA repair defects
Tumour suppressor gene defects

Question 23

Which cells have mutations in leukaemia?

Answer 23

Pluripotent haematopoietic stem cell
Myeloid 
Lymphoid
Pre-B
Pre-T