Leukamogenic Mechanisms & Therapeutics Flashcards
What cytokines and growth factors maintain the haematopoietic stem cells
SCF
FLT-3
What cytokines and growth factors maintain the Common Myeloid Progenitoy
IL-3
GM-CSF
What does PU.1 stimulate
Granulo and monopoieisis
What does GATA.1 stimulate
Erythropoiesis
What transcription factors does PU.1 Stimulate
GM-CSFR, G-CSFR and M-CSFR
What transcription factors does GATA1.1 stimulate
Increases EpoR –> Increases alpha and beta globlins
What congenital syndromes increase the risk of leukaemia
Downs - increases the risk by 20-30 fold
Fanconis Anaemia
Klinefelters disease
Describe the two different prognostic mutations seen in AML
t(15;17) = 81% 10 year survival inv(3)/t(3:3) = 3% 10 year survival
Describe the mutation seen in RUNx1-RUNX1T1
t(8:21)(q22:q22)
What is the RUNX1 gene
It is on Chr21, encodes a TF that binds with CBF and recruits transcriptional activation compotents
What genes does RUNX1 regulate
IL-3
GM-CSF
M-CSF
Where is the RUNT domain of RUNXI
Binds the majority of transcription factors e.g. PU.1 and GATA.1
Where is the activation domain of RUNXI
At the C - terminus
What is the RUNX1T1 gene
On Chr 8, it is a transcriptional co-repressor
It has little function in normal haematopoietic development
What effect does the RUNX1-RUNX1T1 fusion protein have
Distrubs the Pu.1/Gata checkpoint and blcoks myeloid differentiation
Is the RUNX1-RUNX1T1 protein sufficient for AML
NO
What is the translocation in PML-RAR
t(15:17)
What is the PML Gene
Forms PML Nuclear bodies in the nucleus
ALternative splicing of the C terminus produces many different forms of PML
What PML isoform is important to bind PU.1
PML IV
This promotes CEBP Transcription and promotes granulocyte differentiation
What happens in the absence of retinoic acid with RAR
Rar alpha is a potent repressor of transcription
How does the PML-RAR fusion protein cause AML
PML-RAR homodimers bind and repress RAR alpha targets through enhanced recruitment of co-repressors
Blocks granulocyte differentiation at the promyeleotic stage
What type of cancer is caused in a t(15:17) Location
APML
How does retinoic acid treat APML
Coverts PML-RAR into a transcriptional activator and restores differentiation
Is PML-RARalpha sufficient to cause cancer
it is suficient to cause leukaemogenesis!
How do you treat PML-RARalpha
ATRA and arsenic
BUT can get differentiation syndrome
What translocation occurs in CML
t(9:22) forms the bcr-abl fusion protein
What is the abl protein
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
What is the bcr protein
The break point cluster
Signalling protein with unknown normal function
GTPase that displays Ser/Thr activity
What does the bcr-abl protein do
The BCR sequence increases the activity of the abl kinase
multiple downstream pathways also affected: activates Ras and Jakstat pathways
Is the bcr-abl protein sufficient for CML
It is sufficient to cause CML but further mutations are needed for a blast crisis
Why is it though the ALL subtypes might not share common regulatory mechanisms
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
What gene susceptibilities can increase the risk of ALL
ARID5B and CEBPE
What mutation conveys a poor prognsosi in ALL
IZKF1 mutations
What are some mutations in ALL
BCR-ABL
RUNX1-EV6
MLL Rearrangements
MYc Rearrangements
What is a favourable prognosis of ALL
RUNX1-EV6 –> however this is less common in adults
What is the most common lenght of the RUNX1-TUNX1-T! fusion protein
752 a.a.
Which RUNXI-RUNX1TT1 isoform is though to be sufficient to cause AML
RUNX1-ETO9a isoform
Which important gene can the RUNXI fusion protein regress
ARF
