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
