Blood cell abnormalities

Question 1

What is leukaemia? How is it classified?

Answer 1

• It is a type of cancer within the bone marrow whereby certain cells proliferate uncontrollably.
• It arises from mutations in a precursor of myeloid or lymphoid cells.
• Leukaemias are therefore described as being myeloid or lymphoid.
• Myeloid can include precursors of granulocytes, monocytes and also cells of erythroid and megakaryocyte lineages.

Question 2

How does Leukaemia differ from many other cancers?

Answer 2

Leukaemia differs from many other cancers in that the abnormal cells circulate in the bloodstream and migrate into various tissues.

Question 3

Why is it difficult to apply the concept of local invasion and metastasis for leukaemia?

Answer 3

• The terms are usually used to describe solid tumours but cell populations affected by leukaemia are normally mobile.
• The formation of localised tumour masses is also not inevitable in leukaemia, at least not in the earlier stages of the disease.

Question 4

What terms are used instead of malignant and benign for leukaemia? How can you characterise leukaemias using the other terms?

Answer 4

• The clinical behaviour of different types of leukaemia and the degree of their malignancy is described by: acute and chronic.
• Acute leukaemia is one that, if untreated, has profound pathological effects and leads to death in a matter of days, weeks or months.
• Chronic leukaemia is one that causes less impairment of the function of normal tissues and, although it will eventually lead to death, this usually does not occur for a number of years.

Question 5

How can you classify Leukaemias both in terms of origin and malignancy?

Answer 5

Leukaemias can therefore be acute or chronic, lymphoid or myeloid, permitting a simplified classification, which will suffice for our purpose.

Question 6

Why does Leukaemia occur?

Answer 6

• From a number of mutations occurring in protooncogenes (or oncogenes or tumour suppressor genes) of a primitive cell that, as a result, has a growth or survival advantage over normal cells that have not undergone mutation.
• That single cell gives rise to a clone that steadily replaces normal cells.
• The abnormal behaviour of the leukaemic clone can include growth that occurs without dependence on growth factors, continued proliferation without maturation, and a failure to undergo normal cell death (apoptosis).

Question 7

What happens when mutations occur in somatic cells as opposed to germline cells

Answer 7

• Mutations in germ cells can be beneficial, neutral or harmful; beneficial germline mutations permit the species to evolve.
• Mutations in somatic cells are rarely useful or beneficial. They can be neutral or positively harmful, in the latter case sometimes the cell just dies but sometimes the mutation leads to leukaemia or other cancer.
• This process of mutation in a somatic cell may be the result of undetected exposure to mutagens or it may be a random, spontaneous process. The older a person is the more likely it is that enough spontaneous or induced mutations to have accumulated in a single cell for the cell to expand into a clone that replaces normal cells.

Question 8

When does acute myeloid leukaemia occur and what does this suggest?

Answer 8

• Acute myeloid leukaemia (AML) occurs in late middle and old age which can often be demonstrated to be the result of multiple sequential mutations.
• Leukaemia is in part the result of spontaneous mutations—an inevitable feature of our ability as a species to change through evolution—and, in part, a consequence of exposure to environmental mutagenic influences that increase the rate of mutation considerably above the natural baseline rate.

Question 9

What causes leukaemia in infants?

Answer 9

• Somatic mutations that start well before birth leading usually to acute lymphoblastic leukaemia, ALL.
• These mutations are known to result from events that occur during fetal development.
• Antigenic stimulation may also be relevant to the development of some forms of ALL. This normally leads to rearrangement of DNA so that antibodies of greater affinity are produced. If the process goes wrong, a lymphoid stem cell may acquire a malignant phenotype.

Question 10

What mutations lead to acute leukaemia?

Answer 10

• Acute leukaemias often result from mutations in genes encoding transcription factors impairing the cells ability to mature. However, the cells continue to proliferate so that there is an accumulation of primitive cells referred to as blast cells, either lymphoblasts or myeloblasts.

Question 11

What mutations lead to chronic myeloid leukaemia?

Answer 11

• In chronic myeloid leukaemia, the mutation involves activation of signalling pathways within the cell (in CML this results from the fusion protein BCR-ABL1 encoded by the t(9;22) Philadelphia chromosome).
• Cells can then proliferate without needing growth factors.
• Cell survival may be prolonged so that there is a steady expansion of the leukaemic clone.
• However maturation still occurs and, in the case of myeloid cells, mature end cells are still able to function.
• The impairment of normal physiological processes is therefore much less than in the acute leukaemias.
• But this results in the steady expansion of a clone of functionally impaired cells as the leukaemic clone replaces normal cells.

Question 12

Why is there variance in different types of Leukaemias?

Answer 12

• Different types of leukaemia differ in their aetiology (study of origin) and in nature of the mutational events
• Ths impacts the nature of the disturbance in maturation, proliferation or both shown by the leukaemic clone.
• They also differ in age of onset, clinical and haematological features and prognosis. For example, acute lymphoblastic leukaemia (ALL) is particularly a disease of childhood, whereas chronic lymphocytic leukaemia predominantly affects the elderly.