Acute leukaemias 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 an 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 can 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 differentiation
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 with RUNX1T1 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 (Acute promyelocytic leukaemia) ?
Translocation 15;17
- What is a characteristic feature of APML (Acute promyelocytic leukaemia)? 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 (core binding factor) leukaemias.
Type 1: sometimes mutated KIT
Type 2: mutations affecting function of CBF
- Which microscopic feature is pathognomonic of myeloid leukaemias?
Auer rods
- Which stain can be used to distinguish myeloid leukaemias from other leukaemias?
Myeloperoxidase
- Name other similar stains (to distinguish myeloid leukaemias from other leukaemias) that are not used as frequently.
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 aleukaemic 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 the leukaemic cells Leave the normal cells unaffected Combination chemotherapy is ALWAYS used Usually given as 4-5 courses (2 x remission induction + 2/3 x 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.
Proto-oncogene 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)
