Acute Leukaemia Flashcards
What is acute leukaemia characterised by?
o Rapid onset
o Early death if untreated (weeks or months)
o Immature cells (blasts)
o Bone marrow failure
anaemia (pallor, fatigue, SoB),
neutropoenia (infections),
thrombocytopaenia (bleeding)
Where do the mutations occur in leukaemia?
• The leukaemias arise due to the presence of mutations at various point in the B and T cell lineages
• 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
o 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
o 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
When do AML present
What chromosomal abnormalities can you get in AML?
Describe chromosomal translocation?
oInversion or translocations (alters the DNA sequence)
- Creates new fusion genes ALL and AML
• Acute Myeloid Leukaemia / AML; t (8; 21) -> RUNX1+RUNX1T1 15% of AML
o Partial block – some mature cells remain
• Core Binding Factor – AML / CBF-AML; Inv (16), t (16; 16) -> fusion gene 12% of AML
o Partial block – some mature ‘eosinophil-type’ cells remain
• Acute Promyelocytic Leukaemia / APML; t (15; 17) -> PML-RARA APML - Abnormally regulates genes ALL
Describe chromosomal duplication
- Common in AML
- Trisomy 8 and Trisomy 21 (gives a predisposition to AML → 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)
Describe chromosomal loss and deletion.
- Common in AML
- 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 molecular abnormalities can occur in chromosomes?
- Point mutations (associated with AML) → 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)
How does maturation differ in AML?
Excess of myeloblasts
AML
Why do people get AML?
- Familial or constitutional predisposition (e.g. Down syndrome)
- Irradiation
- Anticancer drugs
- Cigarette smoking
- Unknown
How does laeukamogenesis occur in AML?
What are the 2 types of abnormalities in AML?
How does differentiation occur?
- 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)
-
Core Binding Factors are…
- Dimeric transcription factor
- Master controllers of haemopoiesis
- Thus, disruption of transcription factor function can result in failure of differentiation – 2 examples:
What happens in core binding factor leukaemia?
What happens in core binding factor leukaemia?
t(8;21) - some maturation
Describe the inversion blocking differentiation in AML?
Describe acute promyelocytic leukaemia with t(15;17)
- Pathophysiology = t (15; 17) → PML-RARA fusion gene
- Causes haemorrhage (e.g. sudden onset bruising or bleeding) – exhibits DIC and hyperactive fibrinolysis
- Slightly later block in maturation than in classic AML
- Most patient can be cured as molecular mechanism understood
- Characterised by an excess of abnormal promyelocytes (Auer rods)
Where does the maturation defect occur in t(15;17)
What are the 2 mutations in acute promyelocytic leukaemia?
What are the 2 mutations in CBF leukaemia?
What difference would you find on investigations?
