HAEM: Acute leukaemia Flashcards
What are the types of leukaemia?
- Acute and chronic
- Lymphoid and myeloid
What are the characteristics of acute leukaemia?
- Rapid onset
- Early death if untreated (weeks or months)
- Immature cells (blasts)
- Bone marrow failure --> anaemia (pallor, fatigue, SoB), neutropoenia (infections), thrombocytopaenia (bleeding)
Where the mutations in leukaemias occur:
- CML occurs at the pluripotent haemopoietic stem cell level because during the chronic phase it is characterised by overproduction of myelocytes, however, when it turns acute, it can then have a lymphoblastic crisis
- I.E. CML —> ALL blast crisis
- AML can also occur at a pluripotent haemopoietic stem cell level meaning that it presents as a myeloid leukaemia but then relapse later on as an acute lymphoid leukaemia
- I.E. AML –> ALL many years later in relapse
- Other AMLs can occur at a multipotent stem cell level or a granulocyte-monocyte precursor level
What type is the top picture?
Myeloid due to granules seen
What is the epidemiology of AML?
- Incidence increases with age (prognosis is worse with increasing age)
- 40% of patients are adults (mainly older adults)
What types of chromosomal abnormalities which can occur in AML?
- Duplication (trisomy)
- Inversion or translocations (alters the DNA sequence)
- Chromosome loss and part-deletion
Describe duplication in AML.
(1) Duplication (trisomy)
Trisomy 8 and Trisomy 21 (gives a predisposition to AML à as seen in TAM in Down’s syndrome)
There is a possible dosage effect associated with these trisomy’s (having 3 copies of a proto-oncogene rather than 2 may be the underlying trigger of the leukaemia)
What type of leukaemia is shown?
- Acute Promyelocytic Leukaemia / APML; t (15; 17) = PML-RARA
Broadly, what are the outcomes of chromosomal inversion of translocation?
- Creation of new fusion genes
- Abnormal regulation of genes
Give some examples of inversion/translocations of chromosomes in AML.
This creates new fusion genes - occurs in ALL and AML
(1)Acute Myeloid Leukaemia / AML; t (8; 21) –> RUNX1+RUNX1T1 ( 15% of AML)
- Partial block – some mature cells remain
(2)Core Binding Factor – AML / CBF-AML; Inv (16), t (16; 16) –> fusion gene (12% of AML)
- Partial block – some mature ‘eosinophil-type’ cells remain
(3)Acute Promyelocytic Leukaemia / APML; t (15; 17) –> PML-RARA (APML)
What are the two most common chromosomal loss/part-deletions in AML? What is the mechanism of leukaemogenesis here?
- MOST COMMON = del (5q) or del (7q)
Leukaemogenesis from…
- Due to loss of tumour suppressor gene
- One copy of an allele may be insufficient for normal haemopoiesis
- Possible loss of DNA repair systems
What are the risk factors for AML?
- Familial or constitutional predisposition (e.g. Down syndrome)
- Irradiation
- Anticancer drugs
- Cigarette smoking
- Unknown
What molecular changes can cause AML?
(a)Many AMLs have aberrations in chromosome count or structure (many patients with the disease have these abnormalities) and may be directly involved in the development of cancer (discussed in previous cards)
(b) Other patients have molecular changes (apparently normal chromosomes):
- Point mutations (associated with AML) à prognostic implications
- Loss of function of tumour suppressor genes
- Partial duplication
- Cryptic deletion (fusion gene forms deletion of tiny bit of DNA and remaining ends joining up)
What is the leukaemogenesis of AML?
Required multiple genetic hits –> _≥_2 interacting molecular defects (synergise to give leukaemic phenotype)
What are type 1 vs type 2 abnormalities involved in leukaemogenesis in AML?
Type 1 Abnormalities = promote proliferation and survival (anti-apoptosis)
- First stage of an acute leukaemia, but cannot drive the acute phenotype by itself
Type 2 Abnormalities = block differentiation (would normally be followed by apoptosis) –> blast accumulation
- Second stage leads to a phenotypic acute leukaemia
- In most AMLs, there is a block in maturation at this point leading to an excess of blast cells
- These cells have an advantage over the normal cells leading to gradual replacement of the normal cells
Why are transcription factors important in differentiation? Give 2 examples of their disruption in AML.
Transcription factors are very important in differentiation as they:
- Bind to DNA
- Alter structure to favour transcription
- Regulate gene expression
Thus, disruption of transcription factor function can result in failure of differentiation – 2 examples:
- (1) t(8; 21)
- (2) inv(16)
What is the role or Core Binding Factors?
- They are dimeric transcription factor
- Master controllers of haemopoiesis
Which chromosomal aberration in AML makes up 15% of all AML?
Translocation 8;21 fuses RUNX1 (encoding CBF-alpha) with RUNX1T1 – 15% of all AML
- Forms a fusion transcription factor which drives the leukaemia
- New TF binds co-repressors rather than co-activators –> partial differentiation block
Which chromosomal aberration in AML makes up 12% of all AML?
Inversion of Chromosome 16 is another mutation that affects CBF-a – 12% of all AML
- Inversion fuses CBF-beta to MYH11 to form a fusion product that cannot bind to the DNA sequence and leads to an arrest in differentiation
- NOTE: in these 2 examples, there is only one chromosome abnormal however, we tend to see a dominant negative effect (when a single abnormal chromosome dominates over the normal one)*
How can APML present acutely?
Sudden DIC could indicate APML
Causes haemorrhage (e.g. sudden onset bruising or bleeding) – exhibits DIC and hyperactive fibrinolysis
This is due to bone marrow failure (?)
What is the mutation in APML?
t (15; 17) –> PML-RARA fusion gene