Genetics in Haematoncology I Flashcards
How do we classify haematological malgnancies
On their lineage and maturity
What are immature haem malignancies called
AML and ALL
What are mature haem malignancies called
Myelo and lymphoproliferative disroders and Myelomas
Why do genetic changes in cancer matter
Diagnosis and prognosis Treatment choice Treatment Response Evidence of progression or transformation Research t oidentify targeted therapeis
How can we identify gene defects
Chromosome level –> Karyotyping and FISH
RNA Level –> rtPCR, quantitiative rTPCR
DNA Level –> Sanger Sequencing, Next generation sequencing PCR
Protein leevel –> phenotype
Who is AML most common in
adults, increasing with age
What occurs in AML
Proliferation of immautre myleoid cells with a block in differentiation
How does AML differ from CML
AML has proliferation of immature myeloid cells with a block in differentiation
CML has proliferation with differentiation of cells with more neutrophils
What are favourable gene translocations in AML
t(8:21)
t(15:17)
What are unfabourale gene translcoation in AML
Generally other deletions
FLT-3-itd
MLL-ptd
What is APML
t(15:17)
How does APML often present
With deranged clotting
What does RAR do
It is a nuclea receptor that helps control myleoid differentiaion
How does PML-RARa cause cancer
PML-RARa binds to RARa targets but recurits corepressors and induces a differentiation block and increaeses self renewal and growth of the leukaemia clone
How does ATRA treat APML
Switches PML-RARa to an active conformtion, replaces repressors with activators and may cause PML-RARa degradation
What epigenetic treatments can be used in AML
1) IDH1/2 inhibitors
2) HDACs and DNMTs
3) FLT3 inhibitors
Why does IDH1/2 mutations contribute to AML
Normally converts isocitrate to A-ketoglutarate but the mutant enzymes convert this to beta-hydroxyglutarate –> causes disruption of gene expression and blocks myeloblast differentiation
What mutations occur in FLT3
25% internal tandem duplications near the juxtamembrane domain
Point mutations at D835 in the activation loop
ARE FLT3 inhibitors good
Good response in clinical trials but relapse after 3 months is frequent
How does imatinib work
Binds to the TP binding pocket of the bcr-abl protein preventing substrate phosphorylation and signalling.
What miRNAs can ATRA upreguate
Let-7 causing granulocyte differentiation
WHat miRNA is associated with drug resistance in paediatric AML
miR125b
What epigenetic modifications does ATRA cause
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
What histone demethylase is downregulated in ATRA resistance cells
Histone demethylase PH58
What is deregulated in NF and AML
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.
What might be a better way to categorise AML tumours
looking at phosphorylation profiles of MOES, ANXA5, EFHD2
