Leukaemia Flashcards
(40 cards)
1
Q
…..
A
- 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 death in people aged 1‒34 years
- One in 45 of the UK population will die of leukaemia, lymphoma or myeloma
2
Q
What is the difference between lymphoma and myeloma?
A
Lymphoma: tumour of lymphoid cells
Myeloma: neoplasma of plasma cells
3
Q
What is leukaemia?
A
Leukaemia is actually a bone marrow disease and not all patients have abnormal cells in the blood, not all patients have circulating tumour cells
4
Q
How does leukaemia occur?
A
- Leukaemia results from a series of mutations in a single lymphoid or myeloid stem cell
- It isn’t sufficient to have a single mutation (normally at least two)
- 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
5
Q
What can a pluripotent haematopoietic stem cell differentiate into?
A
- We start off with a pluripotent haematopoietic stem cell
- It can give rise to both myeloid and lymphoid cells
- These differentiate into specific stem cells (either myeloid or lymphoid SCs)
- Lymphoid SCs give rise to B lymphocytes and T lymphocytes
- Myeloid SCs give rise to cells of the erythroid lineage and other cells
6
Q
Describe how a stem cell mutation can lead to leukaemia
A
- 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
7
Q
What is different about leukaemia compared to other cancers?
A
- Leukaemia is 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
8
Q
What can solid tumours do?
A
- Invasion and metastasis
- Invasion: local spread
- Metastasis: distant spread
9
Q
Why can we not use invasion and metastasis to classify benign and malignant for haematopoietic and lymphoid cells?
A
They travel around the body normally and enter tissues
10
Q
What is the difference between chronic and acute leukaemia?
A
- 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
11
Q
How can leukaemias be classified?
A
- Chronic or acute
- Myeloid and lymphoid
- Lymphoid can be B/T cell
- Myeloid can be granulocytic, monocytic, erythroid or megakaryocytic
- In cancers involving lymphoid cells, we use different terms: lymphoblastic (acute) and lymphocytic (chronic)
12
Q
Give examples of types of leukaemias
A
- Acute lymphoblastic leukaemia (ALL)
- Acute myeloid leukaemia (AML)
- Chronic lymphocytic leukaemia (CLL)
- Chronic myeloid leukaemia (CML)
13
Q
How do people get leukaemia?
A
- 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
- 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
14
Q
Give examples of important leukaemogenic mutations
A
- 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
- 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)
15
Q
Give examples of inherited abnormalities that can lead to leukaemogenesis
A
Down’s syndrome – associated with an increased propensity to ALL and AML
Chromosomal fragility syndromes
Defects in DNA repair
Inherited defects of TSG
16
Q
What are some causes of leukaemogenic mutations?
A
- Irradiation
- Anti-cancer drugs are themselves leukaemogenic
- Cigarette smoking
- Chemicals e.g. benzene
17
Q
What are beneficial and neutral mutations?
A
BENEFICIAL MUTATION: 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.
NEUTRAL: there is a mutation, but it doesn’t give the cell any particular growth or survival advantage, and therefore it doesn’t give rise to leukaemia.
18
Q
The genome, mutation, evolution and leukaemia
A
- Since some mutations that contribute to leukaemogenesis appear to be random events rather than caused by an exogenous influence, they may result from the nature of the human genome
- The human genome is prone to mutation, leading to evolution of the species
- It may be that a side effect of the ability to evolve is that genetic changes may lead to cancer
19
Q
What is seen in terms of cells and maturation in AML? (how is AML different to CML)
A
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)
- 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.
20
Q
Why might there be a low platelet count in leukaemia?
A
- Due to failure of production of normal functioning end cells
- Pathological process called disseminated intravascular coagulation (clotting occurs within circulation)
21
Q
What is the difference between acute and chronic lymphoid leukaemia?
A
- Acute lymphoblastic leukaemia has an increase in very immature cells (lymphoblasts)
- There is a failure of these lymphoblasts to develop into mature T and B cells
- In chronic lymphoid leukaemias, the leukaemic cells are mature, although abnormal
- So in CLL, we see mature T cells or B cells, but they may not be very functional
22
Q
How does leukaemia cause the characteristics of the disease?
A
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: uric acid in the blood is high due to increased breakdown of DNA
- Renal failure: as a result of uric acid depositing in the kidneys
- 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
- There is a high incidence of shingles and herpes zoster in individuals with CLL
- These patients are susceptible to viral, fungal and bacterial infections
23
Q
How does leukaemia affect the immune system?
A
Loss of normal immune function as a result of loss of normal T cell and B cell function:
- This is a feature of chronic lymphoid leukaemia
- In its advanced stages, CLL has quite a profound immunological deficit
- The number of T cells are also reduced, and responses are poor
- There is a high incidence of shingles and herpes zoster in individuals with CLL
- These patients are susceptible to viral, fungal and bacterial infections
24
Q
Who is affected by acute lymphoblastic leukaemia?
What does this mean in term of acquiring mutations?
A
- It is largely a disease of children
- The peak incidence of ALL in childhood is between 2 and 8 years
- Many of these children have been shown to have a first mutation occurring in utero
- A second mutation occurs just before the development of leukaemia
- We know about in utero mutations from the sots of dried blood from the umbilical cord
25
How does the risk of acute lymphoblastic leukaemia change with age?
- The incidence of ALL decreases with age and stays relatively low after the age of 20
- The peak incidence in childhood reduces
- From the age of 50 onwards, there is a slow rise again
- There is a second, lower peak in old age
- The genetic abnormalities underlying the childhood type are different from those underlying the type in middle-aged people and elderly people
26
Clinical features of acute lymphoblastic leukaemia (due to abnormal cell accumulation)?
- 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 of ALL 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)
27
What are the haematological features of acute lymphoblastic leukaemia?
- Leucocytosis with lymphoblasts in the blood (sometimes they are just in the bone marrow)
- Anaemia (normocytic, normochromic)
- Neutropenia
- Thrombocytopenia
- Replacement of normal bone marrow cells by lymphoblasts
28
What investigations are done into acute lymphoblastic leukaemia?
- 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
29
What is immunophenotyping?
- Recognising the antigens expressed on the surface of cells
- It tells us whether cells are of T-lineage or B-lineage
- Within each lineage, we can recognise different stages of maturation of blast cells (which is of some prognostic importance)
- We can tell from the markers on the cell surface which type of lymphocyte they are
- E.g. if CD19 is expressed on the cell surface, it is a B cell
- TDT expressed on the surface: this tells us that the cell is an immature blast cell
30
What is the importance of cytogenic and molecular genetic analysis in leukaemia?
- Cytogenetic/molecular genetic analysis is useful for managing the individual patient
- This is because it gives us information about prognosis
- It helps us to identify oncogenes, and to study their effects
- Cytogenetic/molecular genetic analysis advances knowledge of leukaemia
- This is because it has permitted the discovery of leukaemogenic mechanisms
- When we see hyperdiploidy (a lot more chromosomes than there should be in a diploid cell), this is often associated with a good prognosis
- A reciprocal translocation of chromosomes is associated with a bad prognosis
31
Leukaemogenic mechanisms in acute lymphoblastic leukaemia
- Formation of a fusion gene – this may result from translocation of chromosomes
- 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
32
Cytogenetics of acute lymphoblastic leukaemia - what are the changes in the chromosome
How can these changes be detected?
- Normal chromosomes 12 and 21 carry the ETV6 gene and RUNX1 gene respectively
- Following translocation, there is a fusion ETV6- RUNX1 gene on chromosome 12
t(12;21)(p12;q22) leading to a ETV6-RUNX1 fusion gene
- Another example: t(10;14)(q24;q11)—the TCL3 gene is dysregulated by proximity to the TCRA gene
- This can be detected by two fluorescent probes, a green probe for ETV6 and a red probe for RUNX1; when a fusion gene is formed the two colours fuse to give a yellow fluorescent signal
- This technique is called fluorescence in situ hybridization —FISH
33
How is acute lymphoblastic leukaemia treated?
- Supportive treatment: red cell transfusion (anaemia), platelets (thrombocytopenia) and antibiotics
- Systemic chemotherapy (orally or intravenous)
- Intrathecal chemotherapy (lumbar puncture, injection of drugs into the CSF)
- Leukaemic cells cross into the CSF
- Giving only systemic chemotherapy cures systemic disease, but there can be relapse from CSF disease
34
How has the survival rates from leukaemia changed over time and why?
- Survival in the 1960s was 3%
- It is getting higher and higher (over 80% in 1996)
- This results from better supportive care, better drugs and better prognostication
35
What is event free survival?
This is survival, in which there is no relapse of the leukaemia. Overall survival refers to whether the patient is alive or not
36
What causes the disease characteristics of leukaemia?
- Proliferation of leukaemic cells
| - Loss of function of normal cells
37
Why must leukaemia treatment be systemic?
- Unlike other cancers, leukaemia is disseminated from very early in the disease process
- Treatment must therefore be systemic
38
....
- Acute lymphoblastic leukaemia results from mutation in a T- or B-lineage lymphoid stem cell
- ALL is not a single disease or even two diseases
- There are multiple different leukaemogenic mechanisms giving different disease phenotypes
39
In CML what is mutated and what effect does this have?
- 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
40
What does epidemiology suggest about leukaemia and what is associated with it?
- Epidemiology suggests that B-lineage ALL may result from delayed exposure to a common pathogen or, conversely, that early exposure to pathogens protects
- Evidence relates to family size, new towns, socio-economic class, early social interactions, and variations between countries
- A study suggested that enterovirus infection gave protection
- Epidemiology also suggests that some leukaemias in infants and young children result from:
Irradiation in utero may be leukaemogenic, in utero exposure to certain chemicals
- EBV may be causative, but the evidence is not very strong
- Rarely, ALL results from exposure to a mutagenic drug
