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Cancer Mechanisms and Therapeutics > Leukamogenic Mechanisms & Therapeutics > Flashcards

Leukamogenic Mechanisms & Therapeutics Flashcards

1
Q

What cytokines and growth factors maintain the haematopoietic stem cells

A

SCF

FLT-3

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2
Q

What cytokines and growth factors maintain the Common Myeloid Progenitoy

A

IL-3

GM-CSF

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3
Q

What does PU.1 stimulate

A

Granulo and monopoieisis

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4
Q

What does GATA.1 stimulate

A

Erythropoiesis

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5
Q

What transcription factors does PU.1 Stimulate

A

GM-CSFR, G-CSFR and M-CSFR

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6
Q

What transcription factors does GATA1.1 stimulate

A

Increases EpoR –> Increases alpha and beta globlins

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7
Q

What congenital syndromes increase the risk of leukaemia

A

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

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8
Q

Describe the two different prognostic mutations seen in AML

A 
t(15;17) = 81% 10 year survival
inv(3)/t(3:3) = 3% 10 year survival
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9
Q

Describe the mutation seen in RUNx1-RUNX1T1

A

t(8:21)(q22:q22)

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10
Q

What is the RUNX1 gene

A

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

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11
Q

What genes does RUNX1 regulate

A

IL-3
GM-CSF
M-CSF

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12
Q

Where is the RUNT domain of RUNXI

A

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

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13
Q

Where is the activation domain of RUNXI

A

At the C - terminus

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14
Q

What is the RUNX1T1 gene

A

On Chr 8, it is a transcriptional co-repressor

It has little function in normal haematopoietic development

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15
Q

What effect does the RUNX1-RUNX1T1 fusion protein have

A

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

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16
Q

Is the RUNX1-RUNX1T1 protein sufficient for AML

A

NO

17
Q

What is the translocation in PML-RAR

A

t(15:17)

18
Q

What is the PML Gene

A

Forms PML Nuclear bodies in the nucleus

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

19
Q

What PML isoform is important to bind PU.1

A

PML IV

This promotes CEBP Transcription and promotes granulocyte differentiation

20
Q

What happens in the absence of retinoic acid with RAR

A

Rar alpha is a potent repressor of transcription

21
Q

How does the PML-RAR fusion protein cause AML

A

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

22
Q

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

A

APML

23
Q

How does retinoic acid treat APML

A

Coverts PML-RAR into a transcriptional activator and restores differentiation

24
Q

Is PML-RARalpha sufficient to cause cancer

A

it is suficient to cause leukaemogenesis!

25
Q

How do you treat PML-RARalpha

A

ATRA and arsenic

BUT can get differentiation syndrome

26
Q

What translocation occurs in CML

A

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

27
Q

What is the abl protein

A

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

28
Q

What is the bcr protein

A

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

29
Q

What does the bcr-abl protein do

A

The BCR sequence increases the activity of the abl kinase

multiple downstream pathways also affected: activates Ras and Jakstat pathways

30
Q

Is the bcr-abl protein sufficient for CML

A

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

31
Q

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

A

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

32
Q

What gene susceptibilities can increase the risk of ALL

A

ARID5B and CEBPE

33
Q

What mutation conveys a poor prognsosi in ALL

A

IZKF1 mutations

34
Q

What are some mutations in ALL

A

BCR-ABL
RUNX1-EV6
MLL Rearrangements
MYc Rearrangements

35
Q

What is a favourable prognosis of ALL

A

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

36
Q

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

A

752 a.a.

37
Q

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

A

RUNX1-ETO9a isoform

38
Q

Which important gene can the RUNXI fusion protein regress

A

ARF

Cancer Mechanisms and Therapeutics (10 decks)

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