Genetics Of Leukemia

Question 1

Why do leukaemia share similar genetic risks

Answer 1

All in same tissue type (bone marrow where haematopoiesis occurs)

Question 2

Which lineage does AML and CML stem from

Answer 2

Myeloid progenitor lineage from haematopoietic stem cells

Question 3

Which leukaemia occurs in the early lymphocyte / lymphoid progenitor

Answer 3

ALL

Question 4

Where do b cell leukaemias usually occur eg Hodgkin,multiple myeloma and CLL

Answer 4

germinal centre

Question 5

What happens in a terminal centre

Answer 5

Class switching
Clonal expansion
Somatic hypermutation
Differentiation

Question 6

Why is the germinal centre at risk of tumorigenesis

Answer 6

Reduced dna damage responses, cell cycle checkpoints and differentiation keeps them in a plasmablastic cell state

Question 7

What suppresses these things

Answer 7

Bcl6

Question 8

Which plasma cell regulators allow differentiation

Answer 8

Irf4 and prdm1

Question 9

Constitutional variants increase risk at start. What happens over course of disease like cll

Answer 9

Somatic mutations become more important

Question 10

Give examples of somatic mutations

Answer 10

Tp53, atm (both tumour suppressors)

Question 11

What did the study on if constitutional variants in cll affect progression find

Answer 11

They didn’t except c6orf106 and another gene on chr10

Ie irf4 didn’t

Question 12

What is the most aggressive form of cll and what types of mutations important

Answer 12

Richter syndrome

Notch1 increased signalling and mutated tp53

= dysregulsted cell cycle, proliferation and lack of apoptosis (due to notch1)

Question 13

Does having cll in family cause a familial risk for other b cell cancers like hodgkins and all

Answer 13

Yes, they share genetic susceptibility (fr)

Question 14

Does having aml increase cancers of the same cell type

Answer 14

Yes

Question 15

Why doesn’t cml

Answer 15

95% is caused by the Philadelphia chromosome not genes

Question 16

Are cancers sometimes monogrnic

Answer 16

Very rarely get high penentrance variants

Question 17

Give example of germline variants eg family passage (monogenic)

Answer 17

Cebpa (see fr on family) - can also be somatic

Pot1

These are both extremely rare as germ line mutants

Question 18

Can pot1 be somatic too

Answer 18

Yes can be acquired and cause both myeloid and lymphoid cancers

(FR)

Question 19

What does pot1 do

Answer 19

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

Question 20

Cll is very polygenic. Many points in the Manhattan but which is most important risk

Answer 20

Irf4

Question 21

In low Irf4 expression due to the variant, what happens which propagates cll

Answer 21

Low Irf4 allows for bcr signalling and therefore survival and cell proliferation of cll

Usually in high Irf4 this bcr signal is blocked

Question 22

Why is aml so complex

Answer 22

Can be caused by somatic mutations, mutations associated with other diseases with secondary aml, chromosomal translocations

Question 23

Give an example of how a mutation is linked to a disorder with secondary aml

Answer 23

Tbx1 linked to platelet disorders with aml

Question 24

Which group on genome has been linked to cll , aml and other cancer susceptibility

Answer 24

Hla

Question 25

Why is hla important in cancers

Answer 25

1/7 of cancers caused by infection
Important in presenting neoantigens from cancers

Question 26

What are the neoantigens in aml

Answer 26

Npm1 and flt3 (pepetides often mutated in aml)

Question 27

Give an example of a xancer lymphoma caused by ebv

Answer 27

Hodgkins

Question 28

Which cancers share genetic susceptibilities as both have pot1 variants

Answer 28

Hodgkin and cll