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?
(Acute Promyelocytic leukaemia)
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
