Genetics of Leukaemia Flashcards
Where is it speculated chronic lymphocytic leukaemia come from?
Late memory B cells.
How many mistakes are made per cell division?
120,000 mistakes per cell division
What is a somatic mutation?
Mistakes made during cell divsion
What is the biggest cause of damage in DNA?
Molecular oxygen which is an atom acceptor during the production of ATP.
What mutations are often common in cancer?
p53 and deletions of chromosome 13
What is preleukemic lymphocytosis?
Precursor conditions some similar symptoms.
What is the inheritance pattern for haematological cancers?
Runs in family.
What is the link of frequency in population to penetrance?
Indirectly proportionate.
Can Acute myeloid leukaemia (AML) be a monogenic disease?
YES
What kind of risk genes are mutated somatically?
CEPBA
RUNX1
Which risk genes are responsible for human syndromes, with AML as a component?
FANCA
TP53
How many loci carrying common variants account for 25% of heritable risk of
Chronic Lymphocytic Leukaemia (CLL)
Which gene is the strongest for CLL?
IRF4
What is the role of IRF4?
B cell development, when under expressed leads to CLL.
What else does IRF4 carry a risk for?
Hodgkin lymphoma
Which of AML and CLL is more complex?
AML
Which is the biggest risk gene for AML?
KMT5B and HLA
Within the genome where do most GWAS map risk variants?
Noncoding regions.
How do noncoding regions affect disease risk?
By altering gene expression.
How do non coding regions alter gene expressions?
- enrichment of active promoters/enhancers
- enrichment for TF binding sites
Where are the TFs with a role in B cell function and development?
- BCR signalling
- apoptosis
- differentiation
What kind of pathway do low levels of IRF4 TF lead to?
BCR activation
CLL cell survival
via phosphorylation of IKAROS and SYK.
Where is the HLA complex?
Within the 6p21.3 region of the short arm of chromosome 6.
How many genes does the HLA complex CONTAIN?
> 240 genes of diverse functions.
What is the main role of the HLA complex?
Many of the genes encode immune
system proteins.
What is the role of HLA antigens on their specialized immune cells?
Present peptides from foreign substances to effector cells of the immune system
How many cancers are caused by infection?
1 in 7
What is the purpose of NPM1 mutations?
They create a targetable shared neoantigen in AML.
Why are targetable shared neoantigen in AML important?
Targeting a mutant NPM1-derived neoantigen has antitumour activity against AML cells?
What are the neoantigens presented on AML red blood cells?
NPM1 mutations create a C-terminal alternative reading frame not present in normal blood cells.
What is the future impact of NPM1 mutant AML?
May be a candidate for neoantigen vaccines or adoptive T-cell therapy.
What happens after a chronic lymphocytic leukaemia diagnosis?
- Time from diagnosis to first treatment is highly variable
- Some patients never need treatment (indolent disease)
- Other patients progress very quickly (aggressive disease)
Which chromosomes are linked to leukaemia progression in CLL?
Chr 6 and chr 10 markers
What is the direct gene linked to CLL progression and aetiological?
C6orf106 (ILRUN)
What is the role of chromosome 10 in disease risk?
Marker for disease progression is
NOT a CLL risk allele
What is the role of LRUN (C6orf106)?
Encodes a protein that functions as an inhibitor of antiviral and pro-inflammatory cytokine transcription.
An example of a monogenic leukaemia gene?
POT1
An example of a polygenic leukaemia gene?
HLA complex
Which leukaemia gene shows shared genetic susceptibility?
IRF4 (chronic lymphocytic leukaemia and Hodgkin lymphoma)
Does IRF4 affect disease progression?
NO
