14. Leukaemia Flashcards
In what age group is leukaemia the most common cancer, and the main cause of cancer death?
- Most common cancer - 15-24 years
* Main cause of cancer death - 1-34 years
What is lymphoma and myeloma?
- Lymphoma - tumour of lymphoid cells
* Myeloma - neoplasma of plasma cells
What is leukaemia?
Cancer of the white blood cells in the bone marrow
Do all leukaemia patients have circulating tumour cells?
No
What brings about leukaemia?
- Series of mutations in a single lymphoid or myeloid stem cells
- Normally at least 2 mutations
- Lead to abnormalities in proliferation, differentiation and cell survival
What cell can give rise to both myeloid and lymphoid cells?
Pluripotent haematopoietic stem cell
What do lymphoid and myeloid stem cells give rise to?
- Lymphoid - B and T lymphocytes
* Myeloid - granulocytic, monocytic, erythroid or megakaryocytic
Outline the first and second mutation in a blood stem cell?
• Initial mutation - growth advantage
- uncontrolled expansion, crowding out the normal polyclonal cells
• Second mutation - even more aggressive behaviour
- can be an interval of years between the 2 mutations
Why can’t leukaemia be defined as benign and malignant and what is used instead?
- Normally, a concept for solid tumours is invasion (local spread) and metastasis
- Neither can be regarded as abnormal behaviour for haematopoeitic and lymphoid cells, as they normally recirculate between tissues and blood
- Described as chronic or acute instead
What is chronic and acute leukaemia?
- Chronic - leukaemias that behave in a relatively benign manner
- Acute - leukaemias that behave in a malignant manner
What are the 4 main types of leukaemia (refer to stem cells and types)?
- Chronic lymphocytic leukaemia (CLL)
- Chronic myeloid leukaemia (CML)
- Acute lymphoblastic leukaemia (ALL)
- Acute myeloid leukaemia (AML)
How can you remember if a lymphoid cell cancer is acute or chronic?
- lymphoCYTIC = chronic
* lymphoBLASTIC = acute
What gene mutations can cause leukaemia?
- Proto-oncogene mutation
- Creation of a novel gene e.g. chimeric
- Translocation may bring a normal gene under the influence of the promoter
- Loss of function of TSG
- Tendency to chromosomal breaks
What inherited or other constitutional abnormalities can contribute to leukaemogenesis?
- Down’s syndrome - increased propensity to ALL and AML
- Chromosomal fragility syndromes
- Defects in DNA repair
- Inherited defects of TSGs
What are environmental causes of leukaemogenic mutations?
- Irradiation
- Anti-cancer drugs (ironic)
- Cigarette smoking
- Chemicals e.g. benzene
Leukaemia can be seen as an acquired genetic disease, resulting from a somatic mutation - mutations can be beneficial or neutral, what does this mean?
- Beneficial - rare, but can lead to reversion to a normal phenotype in some cells in individuals with an inherited abnormality
- Neutral - mutation doesn’t give the cell any particular growth or survival advantage (no leukaemia)
Are mutations that contribute to leukaemogenesis more likely to be random or caused by an exogenous influence?
Random (nature of the human genome - side effect of the ability to evolve)
What generally happens in AML?
- Cells continue to proliferate
- No longer mature - build up of immature cells (myeloblasts) in the BM with spread to the blood
- Failure to produce various end blood cells - can result in anaemia
What are the 2 reasons for a low platelet count in leukaemia?
- Failure of production of normal functioning end cells
* Disseminated intravascular coagulation
What protein is affected by a mutation in AML and CML?
- AML - transcription factors
- CML - signalling protein gene (encodes protein in signalling pathway between a cell surface receptor and nucleus - membrane receptor or cytoplasmic protein)
Are cell kinetics and function more seriously affected in AML or CML?
AML
Does the cell become independent of external signals in AML or CML?
CML
How does the production of end cells differ in AML and CML?
- AML - failure of production of end cells
* CML - increased production of end cells
What is the difference between ALL and CLL?
- ALL - increase in immature cells (lymphoblasts) - failure to develop into mature T and B cells
- CLL - cells are mature, but abnormal
What are the disease characteristics of leukaemia?
- Leucocytosis - blood becomes viscous - blockages
- Bone pain
- Hepatomegaly
- Splenomegaly
- Lymphadenopathy (if lymphoid)
- Thymic enlargement (if T lymphoid)
- Skin infiltration - bumps from leukaemic deposits
What are the metabolic effects of leukaemic cell proliferation?
- Hyperuricaemia - high uric acid in the blood due to increased breakdown of DNA
- Renal failure - uric acid deposition in kidneys (chronic can lead to gout)
- Weight loss
- Low grade fever
- Sweating
What does pallor at the nail beds of an AML patient suggest?
Anaemia
Which leukaemia is an immunological deficit a feature of?
- CLL
- High incidence of shingles and herpes zoster
- Susceptible to viral, fungal and bacterial infections
Which leukaemia is largely a disease of children?
ALL (many have first mutation in utero, and second just before the development of the leukaemia)
How can you tell if an ALL mutation has occurred in utero?
Sots of dried blood from umbilical cord
How does the incidence of ALL change with age?
- Decreases with age
- Stays relatively low after 20yrs
- Slow rise again from 50yrs (second, lower peak in old age)
What does the epidemiology of ALL suggest the cause for it?
- B-lineage ALL may result from delayed exposure to a common pathogen
- Irradiation in utero
- In utero exposure to certain chemicals
- EBV
Can ALL result from exposure to a mutagenic drug?
Rarely - normally causes AML
What are the clinical features of ALL?
- Bone pain
- Hepatomegaly
- Splenomegaly
- Lymphadenopathy
- Thymic enlargement (if T-lineage
- Testicular enlargement
What causes the following features of ALL: • Fatigue • Breathlessness • Fever • Bruising
- Anaemia - fatigue, breathlessness etc.
- Neutropenia - fever, infections etc.
- Thrombocytopenia - bruising, petechiae etc.
What is purpura?
Subcutaenous bleeding - purple-coloured spots in the skin
What do we look for in a x-ray when investigating ALL?
Thymus enlargement and pneumonia
What is immunophenotyping used for in leukaemia?
- Determining whether cells are of T or B-lineage
- Done by recognising antigens expressed on the surface of the cells
- Can recognise different stages of maturation
Which type of analysis is useful for managing the individual leukaemia patient and what does it identify?
- Cytogenic + molecular analysis
- Identify oncogenes
- Information about prognosis
What is an example of a genetic chromosome abnormality in ALL and how could this be detected?
- Chr 12 and 21 carry the ETV6 and RUNX1 gene respectively
- Translocation => fusion ETV6-RUNX1 on Chr 12
- 2 fluorescent probes - green for ETV6 and red for RUNX1 - fusion gene => yellow signal
- This is called fluorescence in situ hybridisation (FISH)
What is the treatment for ALL?
- Red cell transfusion, platelets, and antibiotics
- Systemic chemotherapy (oral or IV)
- Intrathechal chemotherapy (lumbar puncture, injection into CSF)
