Haem: Acute Leukaemia Flashcards
Which cell level does CML tend to occur in?
Pluripotent haematopoietic stem cell
Which cell level does AML tend to occur in?
Pluripotent haematopoietic stem cell or multipotent myeloid stem cell
List some types of chromosomal abnormalities that are associated with AML.
- Duplications
- Loss
- Translocation
- Inversion
- Deletion
How can altered DNA sequence lead to leukaemia?
- By the creation of a fusion gene
- By abnormal regulation of genes
Which chromosomal duplications are most commonly associated with AML?
8 and 21 (there is a predisposition seen in Down syndrome)
List some molecular abnormalities that an occur in apparently normal chromosomes.
- Point mutations
- Loss of function of tumour suppressor genes
- Partial duplication
- Cryptic deletion (formation of a fusion gene by deletion of a small section of DNA)
List some risk factors for AML.
- Familial
- Constitutional (e.g. Down syndrome)
- Anti-cancer drugs
- Irradiation
- Smoking
What are type 1 and type 2 abnormalities with regards to leukaemogenesis?
- Type 1: promote proliferation and survival (anti-apoptosis)
- Type 2: block differentation
NOTE: leukaemogenesis in AML requires multiple genetic hits
What is the main role of transcription factors?
- They bind to DNA, alter the structure to favour transcription and, ultimately, regulate gene expression
- Disruption of transcription factors can result in failure of differentiation
Give an example of how disruption of a transcription factor can lead to leukaemogenesis.
- Core binding factor (CBF) is the master controller of haemopoiesis
- Translocation 8;21 fuses RUNX1 leading to the formation of a fusion gene that drives leukaemia
- The fusion transcription factor binds to co-repressors leading to a differentiation block
- Inversion of chromosome 16 also affects CBF in a similar way
Which chromosomal aberration causes APML?
Translocation 15;17
What is a characteristic feature of APML? Why does this occur?
- Haemorrhage - this is because APML is associated with DIC and hyperactive fibrinolysis
Name the fusion gene that is responsible for APML.
PML-RARA
In what way are the promyelocytes in APML considered ‘abnormal’?
They contain multiple Auer rods
Describe how the variant version of APML is different from the original version.
- The variant form has granules that are below the resolution of a light microscope
- They also tend to have bilobed nuclei
Give a type 1 and type 2 mutation for APML.
- Type 1: FLT3-ITD
- Type 2: PML-RARA
Give a type 1 and type 2 mutation for CBF leukaemias.
- Type 1: sometimes mutated KIT
- Type 2: mutations affecting function of CBF
Which microscopic feature is pathognomonic of myeloid leukemias?
Auer rods
Which stain can be used to distinguish myeloid leukaemias from other leukaemias?
Myeloperoxidase
Name other similar stains that are not used as frequently for myeloid leukaemias (other than myeloperoxidase).
- Sudan black
- Non-specific esterase
List the clinical features of AML.
- Bone marrow failure (anaemia, neutropaenia, thrombocytopaenia)
- Local infiltration (splenomegaly, hepatomegaly, gum infiltration, lymphadenopathy, CNS, skin)
- Hyperviscosity if WBC is very high (can cause retinal haemorrhages and exudates)
Outline the tests that may be used to diagnose AML.
- Blood film
- Bone marrow aspirate
- Cytogenetic studies (done in EVERY patient)
- Molecular studies and FISH
What is aleukaemia leukaemia?
When there are no leukaemic cells in the peripheral blood but the bone marrow has been replaced
Outline the supportive care given for AML.
- Red cells
- Platelets
- FFC/cryoprecipitate in DIC
- Antibiotics
- Allopurinol (prevent gout)
- Fluid and electrolyte balance
- Chemotherapy
What are the principles of treatment of AML?
- Damage the DNA of leukaemic cells
- Leave the normal cells unaffected
- Combination chemotherapy is ALWAYS used
- Usually given as 4-5 courses (2x remission induction + 2/3x consolidation)
- Treatment usually lasts around 6 months
List some determinants of prognosis in AML.
- Patient characteristics
- Morphology
- Immunophenotyping
- Cytogenetics
- Response to treatment
Outline the clinical features of ALL.
- Bone marrow failure
- Local infiltration
What is a key difference in the origin of B-lineage and T-lineage ALL?
- B-lineage starts in the bone marrow
- T-lineage can start in the thymus (which may be enlarged)
List some possible leukaemogenic mechanisms in ALL.
Protooncogene dysregulation due to chromosomal abnormalities (resulting in fusion genes, altered gene promoters)
List some investigations used in the diagnosis of ALL.
- FBC and blood film
- Bone marrow aspirate
- Immunophenotyping
- Cytogenetic/molecular analysis
What are the four phases of chemotherapy for ALL?
- Remission induction
- Consolidation and CNS therapy
- Intensification
- Maintenance
How long does chemotherapy for ALL usually take? Why is it longer in boys?
2-3 years
Longer in boys because the testes are a site of accumulation of lymphoblasts
Who receives CNS-directed chemotherapy? How can this be given?
- All patients should receive CNS-directed chemotherapy
- This can be given intrathecally or a high dose of chemotherapy could be given such that it penetrates the BBB
Outline the supportive care for ALL.
- Blood products
- Antibiotics
- General medical care (central line, gout management, hyperkalaemia management, sometimes dialysis)
