Cancer 14: Cancer as a disease - Leukaemia

Question 1

What is leukaemia?

Answer 1

• Leukaemia is cancer of the blood. It is a disease of the bone marrow. Not all patients have abnormal cells in the blood
• 5% of all cancers are cancers of the blood

In the UK approximately 60 people every day are diagnosed with a cancer of the blood. Blood cancers are the most common cancers in men and women aged 15‒24

They are the main cause of cancer death in people aged 1‒34 years

Question 2

What causes leukaemia?

Answer 2

• Series of mutations in a single lymphoid or myeloid stem cell

These mutations lead the progeny of that cell to show abnormalities in proliferation, differentiation or cell survival leading to steady expansion of the leukaemic clone.

Random error - chance events - that occur through life.

Question 3

Where can mutations occur along the development of white cells?

Answer 3

Acute myeloid leukaemia - muation in myeloid stem cell
Ect.

See slide 14

You get an emergence of a leukaemic clone

Question 4

What is different about leukaemia?

Answer 4

Leukaemia is different from other cancers as most cancers exist as a solid tumour.

However, it is uncommon for patients with leukaemia to have tumours
More often they have leukaemic cells replacing normal bone marrow cells and circulating freely in the blood stream

Leukaemia is different from other cancer because haemopoietic and lymphoid cells behave differently from other body cells.

Normal haemopoietic stem cells can circulate in the blood and both the stem cells and the cells derived from them can enter tissues

Normal lymphoid stem cells recirculate between tissues and blood

The concepts of invasion and metastasis cannot be applied to cells that normally travel around the body and enter tissues

We have to have other ways of distinguishing a ‘benign’ condition from a ‘malignant’ condition and haematologists usually use different words for these concepts

Question 5

Describe leukaemias that behave in a benign manner

Answer 5

Chronic—that means the disease goes on for a long time

Question 6

Describe leukaemias that behave in malignant manner

Answer 6

acute—that means that, if not treated, the disease is very aggressive and the patient dies quite rapidly

Question 7

How is leukaemia classified?

Answer 7

It follows from what has been said that leukaemia can be acute or chronic

Depending on the cell of origin, it can also be lymphoid or myeloid

Lymphoid can be B or T lineage

Myeloid can be any combination of granulocytic, monocytic, erythroid or megakaryocytic

Acute lymphoblastic leukaemia (ALL)
Acute myeloid leukaemia (AML)
Chronic lymphocytic leukaemia (CLL)
Chronic myeloid leukaemia (CML)

Note: lymphoblastic
lymphocytic

Question 8

What are the different types of mutation in leukamia?

Answer 8

Mutation in a known proto-oncogene

Creation of a novel gene, e.g. a chimaeric or fusion gene

Dysregulation of a gene when translocation brings it under the influence of the promoter or enhancer of another gene

Loss of function of a tumour-suppressor gene can also contribute to leukaemogenesis—this can result from deletion or mutation of the gene

If there is a tendency to increased chromosomal breaks, the likelihood of leukaemia is increased

In addition, if the cell cannot repair DNA normally, an error may persist whereas in a normal person the defect would be repaired

Question 9

What inherited conditions predispose leukaemia?

Answer 9

Down’s syndrome
Chromosomal fragility syndromes
Defects in DNA repair
Inherited defects of tumour-suppressor genes

Question 10

What are some identifiable causes of leukaemogenic mutations?

Answer 10

Irradiation
Anti-cancer drugs
Cigarette smoking
Chemicals—benzene

Question 11

What is the difference between acute and chronic myeloid leukaemia?

Answer 11

In AML, cells continue to proliferate but they no longer mature so there is::

• A build up of the most immature cells — myeloblasts or ‘blast cells’—in the bone marrow with spread into the blood
• A failure of production of normal functioning end cells such as neutrophils, monocytes, erythrocytes, platelets (for 2 reasons)
• In AML, the responsible mutations usually affect transcription factors so that the transcription of multiple genes is affected
  Often the product of an oncogene prevents the normal function of the protein encoded by its normal homologue
  Cell behaviour is profoundly disturbed

In CML, the responsible mutations usually affect a gene encoding a protein in the signalling pathway between a cell surface receptor and the nucleus
The protein encoded may be either a membrane receptor or a cytoplasmic protein
- In CML, cell kinetics and function are not as seriously affected as in AML

• However, the cell becomes independent of external signals, there are alterations in the interaction with stroma and there is reduced apoptosis so that cells survive longer and the leukaemic clone expands progressively.

Whereas in AML there is a failure of production of end cells, in CML there is increased production of end cells

Question 12

What are the differences between acute and chronic lymphoid leukaemias?

Answer 12

• Acute lymphoblastic leukaemia has an increase in very immature cells— lymphoblasts—with a failure of these to develop into mature T and B cells
• In chronic lymphoid leukaemias, the leukaemic cells are mature, although abnormal, T cells or B cells

Question 13

How does leukaemia cause the disease characteristics?

Answer 13

Accumulation of abnormal cells leading to:
- Leucocytosis, bone pain (if leukaemia is acute), hepatomegaly, splenomegaly lymphadenopathy (if lymphoid), thymic enlargement (if T lymphoid), skin infiltration

Metabolic effects of leukaemic cell proliferation— hyperuricaemia and renal failure, weight loss, low grade fever, sweating

Crowding out of normal cells leading to
anaemia, neutropenia, thrombocytopenia

Loss of normal immune function as a result of loss of normal T cell and B cell function—a feature of chronic lymphoid leukaemia

Question 14

What are the clinical features of acute lymphoblastic leukaemia?

Answer 14

Resulting from accumulation of abnormal cells:

• Bone pain
• Hepatomegaly
• Splenomegaly
• Lymphadenopathy
• Thymic enlargement
• Testicular enlargement

Resulting from crowding out of normal cells:

• Fatigue, lethargy, pallor, breathlessness (caused by anaemia)
• Fever and other features of infection (caused by neutropenia)
• Bruising, petechiae, bleeding (caused by thrombocytopenia)

Question 15

What are the haematological features of acute lymphoblastic leukaemia?

Answer 15

• Leucocytosis with lymphoblasts in the blood
• Anaemia (normocytic, normochromic)
• Neutropenia
• Thrombocytopenia
• Replacement of normal bone marrow cells by lymphoblasts

Question 16

How do you investigate acute lymphoblastic leukaemia?

Answer 16

Blood count and film
Check of liver and renal function and uric acid
Bone marrow aspirate 
Cytogenetic/molecular analysis
Chest X-ray

You need to see if the cells are B or T lineage

Question 17

Describe cytogenetic and molecular genetic analysis

Answer 17

Cytogenetic/molecular genetic analysis is useful for managing the individual patient because it gives us information about prognosis
Cytogenetic/molecular genetic analysis advances knowledge of leukaemia because it has permitted the discovery of leukaemogenic mechanisms

Question 18

Acute lymphoblastic leukaemia - What are the mechanisms of leukmogenesis?

Answer 18

Formation of a fusion gene
Dysregulation of a proto-oncogene by juxtaposition of it to the promoter of another gene, e.g. a T-cell receptor gene
Point mutation in a proto-oncogene

Question 19

Cytogenetics

Answer 19

See slides

Question 20

How do you treat acute lymphoblastic leukaemia?

Answer 20

Supportive

• Red cells
• Platelets
• Antibiotics

Systemic chemotherapy
Intrathecal chemotherapy