Week 9. Basis and classification of haematological malignancies

Question 1

general info on malignancies?

Answer 1

Monoclonal (polyclonal=reactive events e.g. infections)
Clonal diseases-come from common ancestor.
Cell has mutated leading to malignant transformation.
Excessive proliferation.
Resistant to apoptosis

Question 2

In summary what are the steps causing malignancies?

Answer 2

Toxin, virus infection, drug, genetic predisposition.
Oncogene and tumour suppressor gene
less apoptosis, less differentiation, more proliferation

Question 3

What causes malignancy?

Answer 3

1. Genetic predisposition:
   - downs syndrome- increased incidence of leukaemia.
2. Infection:
   -Viruses-
   human t-lymphotropic virus type 1 (HTLV-1)
   adult t-cell leukaemia/lymphoma (ATLL)
   -Epstein-barr virus- Burkitt’s lymphoma

Bacteria- helicobacter pylori infection0 gastric lymphomas.

(if you’re infected with these, more likely to get cancer later on)

Question 4

A.L.L.

Answer 4

Acute lymphoblastic leukaemia (ALL)

Exposure to mutagens during pregnancy.
Then need a 2nd transforming event after birth. (unclear mechanism)
Children who went to daycare less likely to develop ALL. Seemed exposed to more infections so better immune system so could respond normally to infection and second transforming event.
In twins if one got ALL usually the other did in the end but not at the same age.

Question 5

What environmental things can cause malignancies?

Answer 5

1. Ionizing radiation, cauding mutations
2. Chemicals: benzene (chronic)- chromosomal abnormalities in leukaemia.
3. Drugs: Alkalyting agents, e.g. chlorambucil-myeoloid leukaemia.

Question 6

What is the mechanism of malignancy?

Answer 6

Dysregulation of oncogenes and tumour suppressor genes. Oncogenes gain function, tumour suppressor lose function- can;t suppress

Question 7

Oncogenes

Answer 7

Derived from proto-oncogenes

Gain of function mutation: amplification, point mutations or chromosomal translocations.

Uncontrolled proliferation
Blockage of differentiation OR
Prevention of apoptosis

End up with malignant cells that aren’t fully functional

Question 8

Tumour suppressor genes (TSG)

Answer 8

Commonly involved in cell cycle

Inactivation of a tumour-suppressor gene:

• by deletion or mutation
• loss of function mutations
• promotes malignant transformation

Encode for proteins that negatively regulate proliferation.
p53 most significant TSG in human cancers (50%)

Question 9

Frequent genetic mutations/abnormalities in leukaemia and lymphoma

Answer 9

AML- t(15;17)- oncogene= RARalpha, PML

CML- t(9;22)- oncogene= ABL,BCR

Follicular lymphoma t(14;18) oncogene= BCL-2 to IgH

Question 10

What are the 3 main roles of genetic markers in haematological malignancies?

Answer 10

1. Diagnosis
2. Sub-classification
3. Monitoring minimal residual disease: aim is to put them into remission. May not be free of cancer but below detection.

Question 11

Haematological malignancy diagnosis?

Answer 11

Genetic abnormalities (e.g.t(15;17))
-specific for particular disease.
Clonal immunoglobulin or T cell receptor (TCR) rearrangments.
-determine clonality
-establishing if malignancy is T or B cell lineage.

Question 12

Haematological malignancy sub-classification?

Answer 12

Presence of a particular translocation
t(14;18) in diffuse-large B cell lymphoma
prognastic info for this group of patients

Question 13

Haemattological malignancy montioring minimal residual disease?

Answer 13

Monitoring minimal residual disease:

• low level of disease detactable with some methods
• can have approx. 10^13-10^14 malignant cells
• can use PCR
• patient in remission when less than 5% of blasts detected in the bone marrow.

Question 14

Lab techniques to assess malignant cells?

Answer 14

1. Karyotype analysis: morphological analysis of chromosomes from tumour cells under the microscope
2. Fluorescent in situ hybridization analysis:
   analyse expression of genes, bind specific parts of genome, tags anneal DNA, detect extra copied of genetic material
3. Southern blot analysis: If translocation has occured, will see novel band on gel. Time consuming.
4. PCR: detect chromosomal translocation. Determine presence of clonal cells in B and T cell malignancies.

Question 15

Classifications of haematological malignancy?

Answer 15

WHO classification: morphology and genetic features.
Leukaemia classification uses the FAB classification but also includes molecular genetics.
Primarily classified by lineage- myeloid, lymphoid
Then defined by: morphology, immunophenotype, genetic features, clinical syndromes.