Cancer as a disease - Leukaemia Flashcards
What is the most common cancer in men and women aged 15‒24
Cancers of the blood (i.e. leukaemia)
What is the literal meaning of leukaemia? Why?
‘White blood’
because the first cases of leukaemia recognised had a marked increase in the white cell count which made the blood look whiter
Where does the problem exist in leukaemia?
In the bone marrow (not all patients have abnormal cells in the blood)
What does leukaemia result from?
A series of mutations in a single lymphoid or myeloid stem cell
What are the consequences to the progeny of the mutated cell?
abnormalities in proliferation, differentiation or cell survival leading to steady expansion of the leukaemic clone
Which cells in the lineage can be affected in leukaemia?
Pluripotent haematopoietic stem cell Myeloid stem cell Lymphoid stem cell Pre B lymphocyte Pro T lymphocyte
Describe two ways in which leukaemia is different from other cancers. Hence state why the concepts of invasion and metastasis cannot be applied?
- It is uncommon for patients with leukaemia to have solid tumours instead they have leukaemic cells replacing normal bone marrow cells and circulating freely in the blood stream
- Haemopoietic and lymphoid cells behave differently from other body cells i.e. they circulate the blood and can enter tissues
The concepts of invasion and metastasis cannot be applied to cells that normally travel around the body and enter tissues.
What are the equivalent terms for ‘benign’ and ‘malignant’ used to describe different leukaemias?
Leukaemias that behave relatively benignly are CHRONIC
Leukaemias that behave in a malignant manner are ACUTE – the disease is very aggressive
Hence, describe how leukaemia is classified?
- Leukaemia can be acute or chronic
- Depending on the cell of origin, it can be lymphoid or myeloid
- Lymphoid can be B or T lineage
- Myeloid can be any combination of granulocytic, monocytic, erythroid or megakaryocytic
What are the four main types of leukaemia?
Acute lymphoblastic leukaemia (ALL)
Acute myeloid leukaemia (AML)
Chronic lymphocytic leukaemia (CLL)
Chronic myeloid leukaemia (CML)
Explain the use of the terms ‘lymphoblastic’ and ‘lymphocytic’ in ALL and CLL respectively
In ALL the cells are immature – they are lymphoblasts
IN CLL the cells are mature lymphocytes
What are the important leukaemogenic mutations that have been recognised?
- Mutation in a known proto-oncogene
- Creation of a novel gene e.g. chimeric or fusion gene
- Dysregulation of a gene when translocation brings it under the influence of a promoter or enhancer of another gene
- Loss of function of a tumour-suppressor gene due to deletion/mutation
Based on the important leukaemogenic mutations that have been recognised, state some inherited or other constitutional abnormalities that can contribute to leukaemogenesis.
- Down syndrome
- Chromosomal fragility syndromes
- Defects in DNA repair
- Inherited defects in tumour suppressor genes
What are some identifiable (environmental) causes of leukaemogenic mutations?
Irradiation
Anti-cancer drugs
Cigarette smoking
Chemicals e.g. benzene
Leukaemia can also be seen as what kind of disease?
Leukaemia can be seen as an acquired genetic disease, resulting from somatic mutation
Note that a somatic mutation may be beneficial (reversion to normal phenotype), neutral, or harmful.
Leukaemia may thus be, in part, the inevitable result of the ability of mankind to change through evolution
What type of cell is seen in abundance in acute myeloid leukaemia? What does this abundance lead to?
Immature myeloid cells – the cells continue to proliferate but they no longer mature so there is a build up of immature cells (myeloblasts) in the bone marrow, which spread to the blood
=> a failure of production of normal functioning end cells such as neutrophils, monocytes, erythrocytes, platelets
What do the responsible mutations normally affect in AML?
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
What do the responsible mutations normally affect in CML?
A gene encoding a protein in the signalling pathway between a cell surface receptor and the nucleus
The protein encoded may be a membrane receptor or a cytoplasmic protein
Describe the nature of the leukaemic cells in CML.
These are mature lymphocytes
- their cell kinetics and function are not as seriously affected as they are in AM
- however the cells become 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
How is the production of end cells affected in AML and CML?
AML – decrease in the production of end cells
CML – increase in the production of end cells
What are the metabolic effects of leukaemic cell proliferation?
Hyperuricaemia Renal failure Weight loss Low grade fever Sweating
Which type of leukaemia increases the risk of intraventricular haemorrhage and why?
Acute promyelocytic leukaemia (APML) – this is associated with DIC so the platelet count and fibrinogen are low leading to increased risk of fatal haemorrhage
How can leukaemia cause proliferation of the gums?
Infiltration of leukaemic cells and monocytes can lead to inflammation of the gums
There will be small haemorrhages due to thrombocytopenia
What does epidemiology suggest that B lineage acute lymphoblastic leukaemia may result from?
It may result from delayed exposure to a common pathogen or, conversely, that early exposure to pathogens protects
Acute lymphoblastic leukaemia is largely a disease of?
children
What are some factors that relate to risk of Acute lymphoblastic leukaemia?
Family size, new towns, socio-economic class, early social interactions
Epidemiology also suggests that some leukaemias in infants and young children result from…?
Irradiation in utero
In utero exposure to certain chemicals
What are the clinical features of acute lymphoblastic leukaemia? Result from?
Bone pain Hepatomegaly Splenomegaly Lymphadenopathy Thymic enlargement Testicular enlargement
*These all result from the accumulation of abnormal cells
What are some clinical features of acute lymphoblastic leukaemia that result from the crowding out of normal cells
Caused by anaemia – fatigue, lethargy, pallor, breathlessness
Caused by neutropenia – fever and other features of infection
Caused by thrombocytopenia – bruising, petechiae, bleeding
What investigations are performed in acute lymphoblastic leukaemia?
Blood count and film Check of liver function and renal function and uric acid Bone marrow aspirate Cytogenetic/molecular analysis Chest X-ray
What are the uses of cytogenetic and molecular genetic analysis in ALL?
It is useful for managing the individual patient because it gives us information about prognosis
It permits the discovery of leukaemogenic mechanisms
What are the implications of hyperdiploidy in in the cytogenetic analysis of ALL?
Good prognosis
What features of the cytogenetic analysis are associated with a poor prognosis?
Chromosomal translocations resulting in the formation of a bad fusion gene
What translocation causes ALL? State the fusion gene.
Translocation between chromosome 12 and chromosome 21
Fusion gene: ETV6-RUNX1 on chromosome 12
What technique is used to detect the fusion genes in ALL?
Fluorescence in situ hybridisation (FISH)
What are the treatment options for ALL?
Supportive: red cells, platelets, antibiotics
Systemic chemotherapy
Intrathecal chemotherapy
