Genetics Of Leukemia Flashcards
Why do leukaemia share similar genetic risks
All in same tissue type (bone marrow where haematopoiesis occurs)
Which lineage does AML and CML stem from
Myeloid progenitor lineage from haematopoietic stem cells
Which leukaemia occurs in the early lymphocyte / lymphoid progenitor
ALL
Where do b cell leukaemias usually occur eg Hodgkin,multiple myeloma and CLL
germinal centre
What happens in a terminal centre
Class switching
Clonal expansion
Somatic hypermutation
Differentiation
Why is the germinal centre at risk of tumorigenesis
Reduced dna damage responses, cell cycle checkpoints and differentiation keeps them in a plasmablastic cell state
What suppresses these things
Bcl6
Which plasma cell regulators allow differentiation
Irf4 and prdm1
Constitutional variants increase risk at start. What happens over course of disease like cll
Somatic mutations become more important
Give examples of somatic mutations
Tp53, atm (both tumour suppressors)
What did the study on if constitutional variants in cll affect progression find
They didn’t except c6orf106 and another gene on chr10
Ie irf4 didn’t
What is the most aggressive form of cll and what types of mutations important
Richter syndrome
Notch1 increased signalling and mutated tp53
= dysregulsted cell cycle, proliferation and lack of apoptosis (due to notch1)
Does having cll in family cause a familial risk for other b cell cancers like hodgkins and all
Yes, they share genetic susceptibility (fr)
Does having aml increase cancers of the same cell type
Yes
Why doesn’t cml
95% is caused by the Philadelphia chromosome not genes
Are cancers sometimes monogrnic
Very rarely get high penentrance variants
Give example of germline variants eg family passage (monogenic)
Cebpa (see fr on family) - can also be somatic
Pot1
These are both extremely rare as germ line mutants
Can pot1 be somatic too
Yes can be acquired and cause both myeloid and lymphoid cancers
(FR)
What does pot1 do
Regulates telomere length
Remember than enhancing length of telomeres theory is a prerequisite for cancer cell immortality. Shortening may be tumour suppressive
But shortening of telomeres before telomerase activating can cause cancer promoting genomic instability
Cll is very polygenic. Many points in the Manhattan but which is most important risk
Irf4
In low Irf4 expression due to the variant, what happens which propagates cll
Low Irf4 allows for bcr signalling and therefore survival and cell proliferation of cll
Usually in high Irf4 this bcr signal is blocked
Why is aml so complex
Can be caused by somatic mutations, mutations associated with other diseases with secondary aml, chromosomal translocations
Give an example of how a mutation is linked to a disorder with secondary aml
Tbx1 linked to platelet disorders with aml
Which group on genome has been linked to cll , aml and other cancer susceptibility
Hla
Why is hla important in cancers
1/7 of cancers caused by infection
Important in presenting neoantigens from cancers
What are the neoantigens in aml
Npm1 and flt3 (pepetides often mutated in aml)
Give an example of a xancer lymphoma caused by ebv
Hodgkins
Which cancers share genetic susceptibilities as both have pot1 variants
Hodgkin and cll
