14. Leukaemia Flashcards
Describe the epidemiology of leukaemia.
- Leukaemia is cancer of 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 deathin people aged 1‒34 years
- One in 45 of the UK population will die of leukaemia, lymphoma or myeloma
- Lymphoma: tumour of lymphoid cells
- Myeloma: neoplasma of plasma cells
How does leukaemia come about?
- Leukaemia results from a series of mutations in a single lymphoid or myeloid stem cell
- It isn’t sufficient to have a single mutations (there are normally at least 2)
- The result of mutations is that the cells that the stem cells give rise to differ in their biological properties
- These mutations lead the progeny of that cell to show:
- Abnormalities in proliferation
- Abnormalities in differentiation or cell survival
- This leads to steady expansion of the leukaemic clone
- We start off with a pluripotent haematopoietic stem cell. It can give rise to both MYELOID and LYMPHOID cells. These differentiate into specific cells.
- An initial mutation occurs in a stem cell, giving it a growth advantage
- There is uncontrolled and increased expansion of this stem cell, crowding out the normal polyclonal cells
- A second mutation in one of the cells provides it with EVEN MORE AGGRESSIVE BEHAVIOUR
- There can be an interval of years between the first and second mutations
- E.g. for a lot of leukaemias in childhood, the first mutation occurs in the foetus in utero
Why is leukaemia different from other cancers?
- Most cancers exist as a solid tumour
- However, it is uncommon for patients with leukaemia to have tumours
- 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.
- An important concept for solid tumours is both INVASION and METASTASIS
- Invasion: local spread
- Metastasis: distant spread
- Neither of these can be regarded as ‘abnormal behaviour’ for haematopoietic and lymphoid cells
- These concepts 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
- Haematologists usually use different words for these concepts
Compare chronic and acute leukaemia
- Leukaemias that behave in a relatively ‘benign’ manner are called chronic
- That means the disease goes on for a long time
- Leukaemias that behave in a ‘malignant’ manner are called acute
- That means that, if not treated, the disease is very aggressive and the patient dies quite rapidly
How are leukaemias classified?
- 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)
n cancers involving lymphoid cells, we use different terms: lymphoblastic(acute) and lymphocytic(chronic).
Why do people get leukaemia?
- Leukaemia results from a series of mutations in a single stem cell
- Some mutations results from identifiable (or unidentifiable) oncogenic influences
- Others are probably random errors that occur throughout life and accumulate in individual cells
- Many types of leukaemia increase steadily in incidence with the age of individuals
- This may be because of steady accumulation of mutations, some of which are harmful
What are the most important leukaemogenic mutations?
- Mutation in a known proto-oncogene
- Creation of a novel gene, e.g. a chimeric or fusion gene
- Translocation may bring a normal gene under the influence of the promoter/enhancer of another gene
- Loss of function of a TSG 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
- If cells cannot repair DNA normally, an error may persist (may be the result of an inherited conditions)
- Whereas in a normal person the defect would be repaired
What are inherited or other constituional abnormalities that can contribute to leukamoenesis?
- Down’s syndrome – associated with an increased propensity to Acute Lymphoblastic Leukaemia and Acute Myeloid Leukaemia
- Chromosomal fragility syndromes
- Defects in DNA repair
- Inherited defects of tumour-suppressor genes
What are identifiable causes of leukaemogenic mutations?
- Irradiation
- Anti-cancer drugs are themselves leukaemogenic
- Cigarette smoking
- Chemicals e.g. benzene
Define beneficial mutations.
A rare occurrence but can lead to reversion to normal phenotype in some cells in individuals with an inherited abnormality, e.g. an immune deficiency or bone marrow failure syndrome
Define neutral mutations
there is a mutation, but it doesn’t give the cell any particular growth or survival advantage.
What happens in acute myeloid luekaemia?
In AML, cells continue to proliferate but they no longer mature so there is:
- A build up of the most immature cells (myeloblasts) in the BM with spread into the blood
- A failure of production of normal functioning end cells such as neutrophils, monocytes, erythrocytes, platelets (this can result in ANAEMIA)
What are the causes of low platelet count?
- Due to failure of production of normal functioning end cells
- Pathological process called disseminated intravascular coagulation (clotting occurs within circulation)
Compare acute and myeloid leukaemia.
- In AML, the responsible mutations usually affect TFs, so the transcription of multiple genes is affected
- The product of an oncogene prevents normal function of the protein encoded by its normal homologue
- Cell behaviour is therefore profoundly disturbed
- In CML, the responsible mutations usually affect a signalling protein gene
- This gene encodes 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
- There is reduced apoptosis so that cells survive longer and the leukaemic clone expands progressively
In acute myeloid leukaemia, there is a failure of production of the end cells, whereas in chronic myeloid leukaemia, there is INCREASED production of end cells.
What are the disease characteristics in leukaemia?
Accumulation of abnormal cells leading to:
- Leucocytosis
- Bone pain (if leukaemia is acute) – common in children with ALL
- Hepatomegaly
- Splenomegaly
- Lymphadenopathy (if lymphoid)
- Thymic enlargement (if T lymphoid)
- Skin infiltration
What does this image show?
This is the hand of a patient with AML. There is some pallor at the nail beds, suggesting that there is anaemia. There is also haemorrhage into the skin, as well as a degree of infiltration.
What does this image show?
This patient suffered from an intraventricular haemorrhage. He has acute myeloid leukaemia. AML is associated with DIC, leading to consumption of platelets and clotting factors. There is an increased risk of thrombosis (e.g. pulmonary emboli), but there is an even greater risk of haemorrhage due to the deficiency of platelets and clotting factors.
This shows infiltration into tissues. The patient has AML. We can see haemorrhage into the gums. We can also see enlarged gums – this is due to infiltration by leukaemic cells into the gums. We see this in acute leukaemia with monocytic differentiation. People with poor dentition are more likely to suffer from this.
What are the clinical features of acute lymphoid leukaemia from accumulation of abnormal cells?
- Bone pain is COMMON (particularly in the legs)
- Hepatomegaly
- Splenomegaly
- Lymphadenopathy
- Thymic enlargement (if T lineage)
- Testicular enlargement (due to infiltration of testes)
Many clinical features result 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)
What are the investigations of ALL?
- Before starting investigations, we want a clinical and familial history, and a physical examination
- Blood count and film
- Check of liver and renal function (may be impaired by infiltration) and uric acid measurement
- Bone marrow aspirate – for cytogenetic analysis
- Cytogenetic/molecular analysis
- Chest X-ray – look for thymus enlargement, and to look for evidence of pneumonia
Explain the cytogenetics of acute lymphoblastic leukaemia.
Normal chromosomes 12 and 21 carry the ETV6gene and RUNX1gene respectively
Following translocation, there is a fusion ETV6-RUNX1gene on chromosome 12
t(12;21)(p12;q22) leading to a ETV6-RUNX1fusion gene
Another example: t(10;14)(q24;q11)—the TCL3gene is dysregulated by proximity to the TCRAgene
