Leukamogenic Mechanisms & Therapeutics

Question 1

What cytokines and growth factors maintain the haematopoietic stem cells

Answer 1

SCF

FLT-3

Question 2

What cytokines and growth factors maintain the Common Myeloid Progenitoy

Answer 2

IL-3

GM-CSF

Question 3

What does PU.1 stimulate

Answer 3

Granulo and monopoieisis

Question 4

What does GATA.1 stimulate

Answer 4

Erythropoiesis

Question 5

What transcription factors does PU.1 Stimulate

Answer 5

GM-CSFR, G-CSFR and M-CSFR

Question 6

What transcription factors does GATA1.1 stimulate

Answer 6

Increases EpoR –> Increases alpha and beta globlins

Question 7

What congenital syndromes increase the risk of leukaemia

Answer 7

Downs - increases the risk by 20-30 fold
Fanconis Anaemia
Klinefelters disease

Question 8

Describe the two different prognostic mutations seen in AML

Answer 8

t(15;17) = 81% 10 year survival
inv(3)/t(3:3) = 3% 10 year survival

Question 9

Describe the mutation seen in RUNx1-RUNX1T1

Answer 9

t(8:21)(q22:q22)

Question 10

What is the RUNX1 gene

Answer 10

It is on Chr21, encodes a TF that binds with CBF and recruits transcriptional activation compotents

Question 11

What genes does RUNX1 regulate

Answer 11

IL-3
GM-CSF
M-CSF

Question 12

Where is the RUNT domain of RUNXI

Answer 12

Binds the majority of transcription factors e.g. PU.1 and GATA.1

Question 13

Where is the activation domain of RUNXI

Answer 13

At the C - terminus

Question 14

What is the RUNX1T1 gene

Answer 14

On Chr 8, it is a transcriptional co-repressor

It has little function in normal haematopoietic development

Question 15

What effect does the RUNX1-RUNX1T1 fusion protein have

Answer 15

Distrubs the Pu.1/Gata checkpoint and blcoks myeloid differentiation

Question 16

Is the RUNX1-RUNX1T1 protein sufficient for AML

Answer 16

NO

Question 17

What is the translocation in PML-RAR

Answer 17

t(15:17)

Question 18

What is the PML Gene

Answer 18

Forms PML Nuclear bodies in the nucleus

ALternative splicing of the C terminus produces many different forms of PML

Question 19

What PML isoform is important to bind PU.1

Answer 19

PML IV

This promotes CEBP Transcription and promotes granulocyte differentiation

Question 20

What happens in the absence of retinoic acid with RAR

Answer 20

Rar alpha is a potent repressor of transcription

Question 21

How does the PML-RAR fusion protein cause AML

Answer 21

PML-RAR homodimers bind and repress RAR alpha targets through enhanced recruitment of co-repressors
Blocks granulocyte differentiation at the promyeleotic stage

Question 22

What type of cancer is caused in a t(15:17) Location

Answer 22

APML

Question 23

How does retinoic acid treat APML

Answer 23

Coverts PML-RAR into a transcriptional activator and restores differentiation

Question 24

Is PML-RARalpha sufficient to cause cancer

Answer 24

it is suficient to cause leukaemogenesis!

Question 25

How do you treat PML-RARalpha

Answer 25

ATRA and arsenic | BUT can get differentiation syndrome

Question 26

What translocation occurs in CML

Answer 26

t(9:22) forms the bcr-abl fusion protein

Question 27

What is the abl protein

Answer 27

it is a non-receptor tyrosine kinase Distributed in the cytoplasm and nucleus so can shift between compartments to hance many interaction partners It transduces singals from cell surface growth factor and adhesion receptors to regulate the cytoskeleton --> has G Actin binding sites

Question 28

What is the bcr protein

Answer 28

The break point cluster Signalling protein with unknown normal function GTPase that displays Ser/Thr activity

Question 29

What does the bcr-abl protein do

Answer 29

The BCR sequence increases the activity of the abl kinase | multiple downstream pathways also affected: activates Ras and Jakstat pathways

Question 30

Is the bcr-abl protein sufficient for CML

Answer 30

It is sufficient to cause CML but further mutations are needed for a blast crisis

Question 31

Why is it though the ALL subtypes might not share common regulatory mechanisms

Answer 31

As in MLL Rearrangements there is 100% concordance in those under 12 months In those without MLL rearrangements only about 10-15% concordance in monozygotic twins indication other promotional exposures are needed for tumorigenesis

Question 32

What gene susceptibilities can increase the risk of ALL

Answer 32

ARID5B and CEBPE

Question 33

What mutation conveys a poor prognsosi in ALL

Answer 33

IZKF1 mutations

Question 34

What are some mutations in ALL

Answer 34

BCR-ABL RUNX1-EV6 MLL Rearrangements MYc Rearrangements

Question 35

What is a favourable prognosis of ALL

Answer 35

RUNX1-EV6 --> however this is less common in adults

Question 36

What is the most common lenght of the RUNX1-TUNX1-T! fusion protein

Answer 36

752 a.a.

Question 37

Which RUNXI-RUNX1TT1 isoform is though to be sufficient to cause AML

Answer 37

RUNX1-ETO9a isoform

Question 38

Which important gene can the RUNXI fusion protein regress

Answer 38

ARF