Genetics in Haematoncology I

Question 1

How do we classify haematological malgnancies

Answer 1

On their lineage and maturity

Question 2

What are immature haem malignancies called

Answer 2

AML and ALL

Question 3

What are mature haem malignancies called

Answer 3

Myelo and lymphoproliferative disroders and Myelomas

Question 4

Why do genetic changes in cancer matter

Answer 4

Diagnosis and prognosis
Treatment choice
Treatment Response
Evidence of progression or transformation
Research t oidentify targeted therapeis

Question 5

How can we identify gene defects

Answer 5

Chromosome level –> Karyotyping and FISH
RNA Level –> rtPCR, quantitiative rTPCR
DNA Level –> Sanger Sequencing, Next generation sequencing PCR
Protein leevel –> phenotype

Question 6

Who is AML most common in

Answer 6

adults, increasing with age

Question 7

What occurs in AML

Answer 7

Proliferation of immautre myleoid cells with a block in differentiation

Question 8

How does AML differ from CML

Answer 8

AML has proliferation of immature myeloid cells with a block in differentiation
CML has proliferation with differentiation of cells with more neutrophils

Question 9

What are favourable gene translocations in AML

Answer 9

t(8:21)

t(15:17)

Question 10

What are unfabourale gene translcoation in AML

Answer 10

Generally other deletions
FLT-3-itd
MLL-ptd

Question 11

What is APML

Answer 11

t(15:17)

Question 12

How does APML often present

Answer 12

With deranged clotting

Question 13

What does RAR do

Answer 13

It is a nuclea receptor that helps control myleoid differentiaion

Question 14

How does PML-RARa cause cancer

Answer 14

PML-RARa binds to RARa targets but recurits corepressors and induces a differentiation block and increaeses self renewal and growth of the leukaemia clone

Question 15

How does ATRA treat APML

Answer 15

Switches PML-RARa to an active conformtion, replaces repressors with activators and may cause PML-RARa degradation

Question 16

What epigenetic treatments can be used in AML

Answer 16

1) IDH1/2 inhibitors
2) HDACs and DNMTs
3) FLT3 inhibitors

Question 17

Why does IDH1/2 mutations contribute to AML

Answer 17

Normally converts isocitrate to A-ketoglutarate but the mutant enzymes convert this to beta-hydroxyglutarate –> causes disruption of gene expression and blocks myeloblast differentiation

Question 18

What mutations occur in FLT3

Answer 18

25% internal tandem duplications near the juxtamembrane domain
Point mutations at D835 in the activation loop

Question 19

ARE FLT3 inhibitors good

Answer 19

Good response in clinical trials but relapse after 3 months is frequent

Question 20

How does imatinib work

Answer 20

Binds to the TP binding pocket of the bcr-abl protein preventing substrate phosphorylation and signalling.

Question 21

What miRNAs can ATRA upreguate

Answer 21

Let-7 causing granulocyte differentiation

Question 22

WHat miRNA is associated with drug resistance in paediatric AML

Answer 22

miR125b

Question 23

What epigenetic modifications does ATRA cause

Answer 23

causes 80% acetylation at PML-RARa DNA binding sites

Doesnt really change DNA or Histone methylation hence the affects of ATRA appears to be changes in ATRA treatment

Question 24

What histone demethylase is downregulated in ATRA resistance cells

Answer 24

Histone demethylase PH58

Question 25

What is deregulated in NF and AML

Answer 25

SPRED1 –> a negative regualtor of the Ras-MAPK pathway and interacts with nF
This is expressed in haem cells and negatively reglates haematopoiesis –> decreased in many AMLs and overexpression can decrease tumorigenesis.

Question 26

What might be a better way to categorise AML tumours

Answer 26

looking at phosphorylation profiles of MOES, ANXA5, EFHD2