Haem: Acute Leukaemia Flashcards
Define Leukaemia
Uncontrolled proliferation of immature white blood cells - accumulating in bone marrow or blood. Leukaemia arises due to the presence of mutations at various points in B and T cell lineages
Different from lymphomas as lymphomas typically form solid tumours in lymph nodes, thymus and spleen
Outline the types of classifications of Leukaemias
Acute v Chronic
Lymphoid v Myeloid
Characteristics of acute leukaemias
- Rapid onset
- Early death if untreated (weeks, months)
- Immature cells (blasts)
- Bone marrow failure –> anaemia, neutropenia (infections), thrombocytopenia (bleedings)
Which cell level does CML tend to occur in?
Pluripotent haematopoietic stem cell
During the chronic phase it is characterised by overproduction of myelocytes (granulocyte precursors). Over the period where the leukaemic cells are proliferating more rapidly this increases the risk of furthter mutations to occur. If they do occur this causes CML to turn into an Acute crisis.
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
Describe the incidence of AML in terms of age. How does it differ from ALL.
AML: Incidence increases with age (prognosis worsens with age and 40% of patients are adults)
ALL: Childhood cancer
How can mutations that lead to Leukaemia arise
- Majority due to aberrations in chromosome count or structure
- Other patients may have molecular changes (with apparently normal chromosomes)
How can altered DNA sequence lead to leukaemia?
Duplication:
* potential dosage effect - increased copies of proto-oncogenes
Inversion or Translocation:
* By the creation of a fusion gene
* By abnormal regulation of genes
Chromosomal loss
* loss of tumour suppressor gene
* possible loss of DNA repair systems
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 predisposition (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 (leading to blast cell accumulation)
Leukaemogenesis in AML REQUIRES multiple genetic hits (at least one of each type)
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 (type 2 abnormality)
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 rather than co-activators leading to a differentiation block
- Inversion of chromosome 16 also affects CBF in a similar way
What is APML?
Similar leukaemia to AML however development arrest occurs later down the cell line (in promyelocytes - which are granulocyte precursors)
In what way are the promyelocytes in APML considered ‘abnormal’?
They contain multiple Auer rods (as they are hyper granular)
