Cancer as a Disease - Leukaemia Flashcards
X% of all cancers are leukaemias
5
- Blood cancers are the most common cancers in XXX aged x-x
men and women aged 15‒24
main cause of cancer death in people aged 1‒34 years
Leukaemia
- Leukaemias that behave in a relatively ‘benign’ manner are called ….
chronic
- Leukaemias that behave in a ‘malignant’ manner are called …
acute
3 levels of leukaemia classification?
leukaemia can be acute or chronic
- Depending on the cell of origin, it can also be lymphoid or myeloid
lymphoblastic (acute lymphoid, reminds us that they’re lymphoblasts) and lymphocytic (chronic lymphoid of mature lymphocytes)
What lineage are lymphoid cells
B or T lineage
What lineage are myeloid cells
granulocytic, monocytic, erythroid or megakaryocytic
Leukaemia results from a series of mutations in …
a single stem cell
Three important leukaemogenic mutations that have been recognized?
Mutation in a known proto-oncogene making an oncogene
Creation of a novel gene, usually through translocation 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
Inherited or other constitutional abnormalities can contribute to leukaemogenesis, e.g.: (4)
Down’s syndrome – predisposes to ALL and AML
Chromosomal fragility syndromes
Defects in DNA repair
Inherited defects of tumour-suppressor genes
- Identifiable causes of leukaemogenic mutations include: (4)
Irradiation
Anti-cancer drugs
Cigarette smoking
Chemicals e.g. benzene
What happens in AML
- In AML, cells continue to proliferate but they no longer mature so there is:
A build-up of the most immature cells- myeloblasts or ‘blast cells’—in the bone marrow with spread into the blood
A failure of production of normal functioning end cells such as neutrophils, monocytes, erythrocytes, platelets
What are the reasons that there a failure of production of normal functioning myeloid cells in AML
1 – because of maturation arrest, 2 – because of crowding out of normal bone marrow cells
What happens in CML
- In CML, the responsible mutations usually affect a gene encoding 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 and there is reduced apoptosis so that cells survive longer and the leukaemic clone expands progressively
What proteins are affected in CML
Surface receptor or cytoplasmic proteins
2 key differences between AML and CML
in AML there is a failure of production of end cells, in CML there is increased production of end cells
- 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
Clinical symptoms of myeloid leukaemia (7)
Accumulation of abnormal cells leading to:
- Leucocytosis
- Bone pain (if leukaemia is acute)
- Hepatomegaly - this
- Splenomegaly – and this is because they are good environments for proliferation of lymphoid and myeloid cells
- Lymphadenopathy (if lymphoid)
- Thymic enlargement (if T lymphoid)
- Skin infiltration
Metabolic effects of myeloid leukaemia
- Hyperuricaemia
- Renal failure – because the hyperuricaemia leads to uric acid being deposited in the kidneys
- Weight loss
- Low grade fever
- Sweating
Crowding out of normal cells in myeloid leukaemia leads to
- Anaemia
- Neutropenia
- Thrombocytopenia
Acute lymphoblastic leukaemia largely affects …
children
- Epidemiology suggests that B-lineage ALL may result from ….. (2)
delayed exposure to a common pathogen or, conversely, that early exposure to pathogens protects
Evidence for the pathogen exposure idea of ALL causation:
- Evidence relates to family size, new towns (higher rates), socio-economic class (higher classes higher rates), early social interactions (early protected), variations between countries
Epidemiology suggests that some leukaemias in infants and young children result from:
Irradiation in utero
In utero exposure to certain chemicals
Epstein–Barr virus infection (?)
Exposure to a mutagenic drug (rarely)
ACUTE LYMPHOBLASTIC LEUKAEMIA- CLINICAL FEATURES from accumulation of abnormal cells: (6)
Resulting from accumulation of abnormal cells
- Bone pain
- Hepatomegaly
- Splenomegaly
- Lymphadenopathy
- Thymic enlargement
- Testicular enlargement
ACUTE LYMPHOBLASTIC LEUKAEMIA- CLINICAL FEATURES Resulting from crowding out of normal cells: (3)
- Fatigue, lethargy, pallor, breathlessness (caused by anaemia)
- Fever and other features of infection (caused by neutropenia)
- Bruising, petechiae, bleeding (caused by thrombocytopenia)
ACUTE LYMPHOBLASTIC LEUKAEMIA- HAEMATOLOGICAL FEATURES: (5)
- Leucocytosis with lymphoblasts in the blood
- Anaemia (normocytic, normochromic)
- Neutropenia
- Thrombocytopenia
- Replacement of normal bone marrow cells by lymphoblasts
ALL investigations? (6)
- Full clinical history
- Blood count and film
- Check of liver and renal function and uric acid
- Bone marrow aspirate
- Cytogenetic/molecular analysis
- Chest X-ray
What is cytogenetic analysis and what can it be used for?
Looking at chromosomes basically
- Cytogenetic/molecular genetic analysis is useful for managing the individual patient because it gives us information about prognosis
ACUTE LYMPHOBLASTIC LEUKAEMIA- 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
What technique is used to spot fusion genes
FISH - fluorescence in situ hybridization
ALL treatment 3 levels?
- Supportive care
- Systemic chemotherapy
- Intrathecal chemotherapy
