Genetics of Leukaemia

Question 1

Where is it speculated chronic lymphocytic leukaemia come from?

Answer 1

Late memory B cells.

Question 2

How many mistakes are made per cell division?

Answer 2

120,000 mistakes per cell division

Question 3

What is a somatic mutation?

Answer 3

Mistakes made during cell divsion

Question 4

What is the biggest cause of damage in DNA?

Answer 4

Molecular oxygen which is an atom acceptor during the production of ATP.

Question 5

What mutations are often common in cancer?

Answer 5

p53 and deletions of chromosome 13

Question 6

What is preleukemic lymphocytosis?

Answer 6

Precursor conditions some similar symptoms.

Question 7

What is the inheritance pattern for haematological cancers?

Answer 7

Runs in family.

Question 8

What is the link of frequency in population to penetrance?

Answer 8

Indirectly proportionate.

Question 9

Can Acute myeloid leukaemia (AML) be a monogenic disease?

Answer 9

YES

Question 10

What kind of risk genes are mutated somatically?

Answer 10

CEPBA

RUNX1

Question 11

Which risk genes are responsible for human syndromes, with AML as a component?

Answer 11

FANCA

TP53

Question 12

How many loci carrying common variants account for 25% of heritable risk of

Answer 12

Chronic Lymphocytic Leukaemia (CLL)

Question 13

Which gene is the strongest for CLL?

Answer 13

IRF4

Question 14

What is the role of IRF4?

Answer 14

B cell development, when under expressed leads to CLL.

Question 15

What else does IRF4 carry a risk for?

Answer 15

Hodgkin lymphoma

Question 16

Which of AML and CLL is more complex?

Answer 16

AML

Question 17

Which is the biggest risk gene for AML?

Answer 17

KMT5B and HLA

Question 18

Within the genome where do most GWAS map risk variants?

Answer 18

Noncoding regions.

Question 19

How do noncoding regions affect disease risk?

Answer 19

By altering gene expression.

Question 20

How do non coding regions alter gene expressions?

Answer 20

• enrichment of active promoters/enhancers
• enrichment for TF binding sites

Question 21

Where are the TFs with a role in B cell function and development?

Answer 21

• BCR signalling
• apoptosis
• differentiation

Question 22

What kind of pathway do low levels of IRF4 TF lead to?

Answer 22

BCR activation

CLL cell survival
via phosphorylation of IKAROS and SYK.

Question 23

Where is the HLA complex?

Answer 23

Within the 6p21.3 region of the short arm of chromosome 6.

Question 24

How many genes does the HLA complex CONTAIN?

Answer 24

> 240 genes of diverse functions.

Question 25

What is the main role of the HLA complex?

Answer 25

Many of the genes encode immune system proteins.

Question 26

What is the role of HLA antigens on their specialized immune cells?

Answer 26

Present peptides from foreign substances to effector cells of the immune system

Question 27

How many cancers are caused by infection?

Answer 27

1 in 7

Question 28

What is the purpose of NPM1 mutations?

Answer 28

They create a targetable shared neoantigen in AML.

Question 29

Why are targetable shared neoantigen in AML important?

Answer 29

Targeting a mutant NPM1-derived neoantigen has antitumour activity against AML cells?

Question 30

What are the neoantigens presented on AML red blood cells?

Answer 30

NPM1 mutations create a C-terminal alternative reading frame not present in normal blood cells.

Question 31

What is the future impact of NPM1 mutant AML?

Answer 31

May be a candidate for neoantigen vaccines or adoptive T-cell therapy.

Question 32

What happens after a chronic lymphocytic leukaemia diagnosis?

Answer 32

* Time from diagnosis to first treatment is highly variable * Some patients never need treatment (indolent disease) * Other patients progress very quickly (aggressive disease)

Question 33

Which chromosomes are linked to leukaemia progression in CLL?

Answer 33

Chr 6 and chr 10 markers

Question 34

What is the direct gene linked to CLL progression and aetiological?

Answer 34

C6orf106 (ILRUN)

Question 35

What is the role of chromosome 10 in disease risk?

Answer 35

Marker for disease progression is NOT a CLL risk allele

Question 36

What is the role of LRUN (C6orf106)?

Answer 36

Encodes a protein that functions as an inhibitor of antiviral and pro-inflammatory cytokine transcription.

Question 37

An example of a monogenic leukaemia gene?

Answer 37

POT1

Question 38

An example of a polygenic leukaemia gene?

Answer 38

HLA complex

Question 39

Which leukaemia gene shows shared genetic susceptibility?

Answer 39

IRF4 (chronic lymphocytic leukaemia and Hodgkin lymphoma)

Question 40

Does IRF4 affect disease progression?

Answer 40

NO