Cancer 14: Leukaemia Flashcards
Leukaemia epi
5% of all cancers are cancers 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
What does leukaemia mean. What actually is it
‘White blood’ (first cases had increase WCC)
Leukaemia is actually a bone marrow disease and not all patients have abnormal cells in the blood
Leukaemia results from mutations in which cells.
What is the effect
Series of mutations in single LYMPHOID or MYELOID STEM CELL
Lead the progeny of that cell to show abnormalities in:
- Proliferation
- Differentiation
- Cell survival
STEADY EXPANSION OF LEUKAEMIC CLONE
Which blood cells can be involved in leukaemia
Pluripotent haemoatopoietic stem cell
Myeloid stem cell
Lymphoid stem cell
Pre-B lymphocyte
Pro-T lymphocyte
How is lukaemia different to other cancers
Not usually solid (usually leukaemic cells replacing normal bone marrow and circulating freely in blood stream)
Also, normal haematopoietic stem cells circulate in blood. The stem cells and the cells derived from them can enter tissues usually. Also lymphoid cells circulate between tissues and blood. So can’t really apply ‘invasion’ or ‘metastasis’ to cells that enter tissues anyway.
How are leukaemias classified in terms of benign and malignant
We have to have other ways of distinguishing a ‘benign’ condition from a ‘malignant’ condition than invasion
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 is leukaemia classified on cell lineage
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
4 types of leukaemia
Acute lymphoblastic leukaemia (ALL)
Acute myeloid leukaemia (AML)
Chronic lymphocytic leukaemia (CLL)
Chronic myeloid leukaemia (CML)
Note the difference between lymphoblastic (ACUTE) and lymphocytic (CHRONIC)
Outline the type of mutations leading to leukaemia
Series of mutations in single stem cell.
Identifiable:
1. 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
Outline role of TSGs in leukaemia
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
Outline inherited or other constitutional abnormalities contributing to leukaemogenesis
Down’s syndrome
Chromosomal fragility syndromes
Defects in DNA repair
Inherited defects of tumour-suppressor genes
Carcinogens associated with leukaemia
Irradiation
Anti-cancer drugs
Cigarette smoking
Chemicals—benzene
Is leukaemia an acquired genetic disease, or germ cell based
Leukaemia, like cancer in general, can be seen as an acquired genetic disease, resulting from somatic mutation
T.f mutations in both germ cells and somatic cells are always harmful
F
Mutation in germ cells may bring favourable, neutral or unfavourable characteristics to the species
Somatic mutation may be beneficial*, neutral or harmful
Give an example of 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
T/f leukaemia is always linked to an exogenous influence
F
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
Differentiate acute and chronic myeloid leukaemia
What are the two reasons for reduced production of mature cells in ACL
AML:
Cells proliferate, but cannot mature.
-myeloblasts in bone marrow, spreading to blood
-failure of prudction of end cells like neutrophils, monocytes, erythrocytes and platelets
-there is reduced production of these cells because (1. there is a mutation blocking the production of end cells 2. there is crowding out of the other cells)
CML:
Cell becomes independent of external signals. Alterations in ECM stroma interaction. Reduced apoptosis and cells survive longer and leukaemic clone expands
Types of mutations responsible for AML
TFs … so transcription of multiple genes affected
Often, the product of an oncogene prevents normal function of the protein encoded by its normal homologue (i.e. the protooncogene)
Cell behaviour disturbed
Types of mutations responsible for CML
mutations usually affect a gene encoding a protein in the signalling pathway between a cell surface receptor and the nucleus
membrane receptor or cytoplasmic protein
(explains why it is no longer sensitive to external signals)
What happens to end cells in CML and AML
Does the CML mutation (i.e. cystoplasmic or membrane protein) have a worse effect than the AML mutation (i..e in a TF)?
Whereas in AML there is a failure of production of end cells, in CML there is increased production of end cells
No- In CML, cell kinetics and function are not as seriously affected as in AML
Differentiate acute lymphoblastic leukaemia and chronic lymphocytic leukaemia
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
How does leukaemia cause disease characteristics
Acuumulation of abnormal cells
Metabolic effects of leukaemic cell proliferation
Crowding out of normal cells
Loss of normal immune function (in CLL)
How does accumulation of abnormal cells lead to disease characteristics in leukaemia
Leucocytosis,
bone pain (if leukaemia is acute),
hepatomegaly,
splenomegaly
lymphadenopathy (if lymphoid),
thymic enlargement (if T lymphoid),
skin infiltration
How does metabolic effects of leukaemic cell proliferation lead to disease characteristics
hyperuricaemia and renal failure,
weight loss, low grade fever, sweating
How does crowding out of normal cells in lead to disease characteristics in leukaemia
anaemia, neutropenia, thrombocytopenia
Which cuase of disease characteristics is only in CLL
Loss of normal immune function as a result of loss of normal T cell and B cell function—a feature of chronic lymphoid leukaemia
What is leukaemia cutis
Leukaemia in the skin due to small myeloid tumours
Why is the hyperurcaemia, effect in acute and chronic leukaemias
Increased proliferation and break down of RNA etc
can lead to renal damage in acute
gout in chronic
What might be seen in the skin of patients with leukaemia
Small tumours (particularly in chronic disease)
Small haemorrahges (due to thrombocytopenia)/ pallor (due to anaemia) on the skin (slide 41)
What could leukaemia show in the brain
Bleeding.
E.g. in acute promyelocytic anaemia there is thrombocytopaenia due to crowding, AND also DIC
led to interventricular haemorrhage
What could be see in the mouth with leukaemia
In particular myelomonocytic (these cells can get into skin and gums and act like these tissues)
Haemorrhage into gums
Proliferation of tissue in skin and gums
What is the effect of CLL on the immune system + what infection are they at risk of
B lymphocyte neoplasm
Hypo-IgG
Poor response to infections
And poor cell mediated immunity
Including risk of shingles (varicella zoster)
Who is acute lymphoblastic leukaemia most common in
Children up to age 8
(peak age 2-5)
Risk is then much lower until aging,when it increases again
T/F there are distinct genetic mutations resulting in ALL when young and when old
T…..
high risk when young and risk increases a litte as you get old
DIFFERENT GENETIC MUTATIONS
In older people, it’s the same BCR-ABL that cuases CML which is seen in AML but not for kids
Outline possible exposures affecting ALL
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, variations between countries
Enterovirus may protect
T/F high classes are less likely to get ALL
F… they are more likely (less likely to get infections due cramped environemnts)
Other than social factors, which other epidemioloyical factors affect ALL
Irradiation in utero
In utero exposure to certain chemicals ? Baygon, ? Dipyrone
? Epstein–Barr virus infection
Rarely from exposure to mutagenic drug
Why is it important to look at epidemiology with ALL
Because from looking in umbilical cords, you can see that the first mutation has already taken place in utero
Is this random, or due to radiation or something else?
The second hit is acquired during life
Therapy related leukaemias are usually of what type
Mainly myeloid, sometimes lymphoblastic
Clinical feautres of ALL resulting from accumultion of abnormal cells
Bone pain (kids can present with bone pain in limbs)
Hepatomegaly
Splenomegaly
Lymphadenopathy
Thymic enlargement
Testicular enlargement
2 sanctuary sites for ALL which cannot be targeted with chemo
Testes and the CNS
Clinical features of ALL resulting from crowding of normal cells
Fatigue, lethargy, pallor, breathlessness (caused by anaemia)
Fever and other features of infection inc. pneumonia (caused by neutropenia)
Bruising, petechiae, bleeding (caused by thrombocytopenia)
Haematological features of ALL
Leucocytosis with lymphoblasts in the blood (OR maybe not if they still confined to the bone marrow)
Anaemia (type?)
Neutropenia
Thrombocytopenia
Replacement of normal bone marrow cells by lymphoblasts
What type of anaemia is seen in ALL
Normocytic normochromic
Investigations for ALL
Blood count and film
Check of liver and renal function and uric acid
Bone marrow aspirate
Cytogenetic/molecular analysis
Chest X-ray (for thymus tumour? or pneumonia?)
What could be seen in blood film of ALL of the lukaemic cells
Larger than normal
High nucleo-cytoplasmic ratio
Delicate chromatin pattern showing immature cell
Nucleoli showing immature cell
Why is immunophenotyping done
Differentiate between acute lymphoblastic and acute myeloid leukaemia
How can you distunguish acute lymphoblastic and acute myeloid leukaemia
Acute myeloid may have granules with myeloperoxidase inside
Also may have auer rods in AML which are crystalline structure in cytoplasm
Why can granules not be relied on to distinguish acute lymphoblastic and acute myeloid leukaemia
In particularly primative AML cells, the granules may not be present
Then you need to distinguish with immunphenotyping
2 uses for immuniphenotyping
- Diagnosis of whether it is myeoid/lymphoid and then whether it is T or B cell
(different treatments) - Look for minimal residual disease by immunophenotyping blood after treatment, to see if there are cells left in the blood with the same markers as the leukaemic cells that the patient presented with
What could immunophenotyping show
B cell or T cell (e.g. for b cell CD10 and CD19)
TdT is an marker of very immature cells (blast cells)
CD10 is aka
The common ALL antigen
Why is cytogenetic and molecular genetic analysis useful for ALL
Gives info about individual patient for prognosis
Has permitted discovery of leukaemia mechanisms
What would indicated a good and a poor prognosis from cytogenetic analysis of ALL
Good= hyperdiploidy (i.e. having lots of chromosomes is good prognosis so lots of 3 is okay)
Poor=translocations (4;11)
Leukaemogenic mechanisms
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
Outline transolations in ALL
Children:
4;11
p12;q21 (leads to ETV6-RUNX1 fusion gene)
A part of q of 21 sticks onto p of 12
What would be seen in FISH with a single translocation
1 normal of each gene (from the unaffected chromosome)
1 mixed colour
1 residual gene (some of the gene that did not translocated…. see slide 72 makes sense)
What is FISH
Give an example
This technique is called fluorescence in situ hybridization —FISH
e.g.
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
Prognosis for each type of cytogenetic change in ALL
Trisomies (hyperdiploid) and 12;21 good
9;22 (i.e. philadelphia positive which happens in old people is bad, but has improved with tyrosine kinase inhibiors)
Outline a case of cytogenetics with dysregulation of proto-oncogene
Dysregulation of a proto-oncogene by juxtaposition of it to the promoter of another gene, e.g. a T-cell receptor gene
t(10;14)(q24;q11)—the TCL3 gene is dysregulated by proximity to the TCRA gene
Treatment for ALL
Supportive (red cell, platelet ABs)
Systemic chemo
Intrathecal chemo (with lumbar puncture due to CNS being a sanctuary site)
Why has there been improvement in tratment results of ALL
Better supportive care (plateelts, infection etc)
Better chemo
