CE L6 Leukeamias Flashcards
L is cancer of what cell?
WBC
Why is CML the best understood?
Easy to obtain samples
What leads to death in CML
not the presence of the cells but that they proliferae relentlessly and squeeze all functioning cells out of the marrow.
Less RBC - anaemia
Less WBC - infeciton
people die of opportunistic infection
What do CML WBC looklike
immature and blast like
What does a blood sample from CML look like
Normally we have 5% WBC but there is much more in L
What are the three branches haemopoetic cells become?
Myeloid (inate immune)
Erythoid (RBC)
Lymphoid (adaptive immune) - t and b cells
How is L clasified
acute or chronic
depending on cell of origin (myeloid or lymphoid)
Is chronic or acute L worse?
acute
chronic is slower growing so more time to treat
Symptoms (5)
- fatigue, anaemia, enlarged spleen/liver
- elevated WBC count
- all stages of graulocyte differentiation on blood smear
- hypercellularity of the bone marrow
- increased myloid - erythroid raio
Stages of CML
- initial chronic
- Accelerated phase after 4 years
- Acute - blast crisis
What is blase crisis?
no functional WBC
What is mutated in over 50% of acute myeloid leukemias?
Ras
4 Common chromosomal abnormalities in L
addition
translocation (Larger changes)
deletion
amplification
Gross chromosomal changes are a specific feature of L
Studying leukemias revealed ………………. oncogenes
novel - genes that dont exist in normal patietns
95% of CML has what chromosomal feature
reciprocal translocation between chromosomes 9 and 22
95% of CML has what chromosomal feature
reciprocal translocation between chromosomes 9 and 22
- takes just part of the gene so a novel oncogene is formed
What is the name of the novel oncogene from reciprical transformation
BCR-ABL
takes the break point cluster region (BCR) and Abl tyrosine kinase
another name for the BCR-ABL chromosone
philidelphia chromosome - diagnostic marker
What is Abl like in normal cells vs CML
inactive in cells as the regulatory domain folds over it and so the kinase domain is not exposed - when a ligand arrives it phosphorylates the regulatory domain exposing tyrosine kinase,
So in BCR-Abl oncogene you lose regualtion - constituative activity
What is the result of active Abl (3)
Constitutively activates:
Ras pathway
Phosphoinositide-3-kinase pathway
Signal tranducers are activators of transcription (STATs)
Theory about BCR-Abls role in CML
this is initial mutation making it unstable so driving accumulation of further mutations
Why can’t we used mabs to target BCR-Abl?
it’s cytoplasmic - not a receptor so we can’t target with Ab as it’s in the cell and they are too big
Why can’t we used mabs to target BCR-Abl?
it’s cytoplasmic - not a receptor so we can’t target with Ab as it’s in the cell and they are too big
Where is C-Abl found
role of each?
cytoplasmic and nuclear location
nuclear - interacts with p53 and Rb to regulate gene transcription
cytomplasmic - role in cell growth
What is C-Abl activated by
DNA damage
S phase
downstream of intergrin signalling
what is C-abl
non-receptor protein tyrosine kinase
What type of molecule is gleevec?
small synthetic molecule (imatinib mesylate)
How does Glivec work
inhibits proliferation by….
blocking Abl tyrosine kinase, PDGFbetaR and c-kit tyrosine kinase
what is the advantage of Glivec?
relatively few s/e
2 causes of resistance to glivec:
-BCR-Abl amplification
2 causes of resistance to glivec:
- BCR-Abl amplification
- point mutation in BCR abl preventing glivec binding (glivec binds to the inactive from when ATP is not bound but change prevents this)
How long is treatment with Glivec?
lifelong - if you leave once cell behind it could come back
how does resistance develop?
initial drug treatment may select for resistance or resistant clones may exist from the start
What is Dasatinib/nilotinib
2nd generation CML therapies - bind to active confirmation of BCR-abl and can therefore be effective when point mutation has led to glivec resistance
What was the issue with 3rd gen BCR abl inhibitors
there was another mutation so a third gen inhibitor was made against this however it was too cardiotoxic
How can we use gliver for gastrointestinal tumours?
s
How can we use glivec for gastrointestinal tumours?
tumour is driven by constitutive c-kit recptor activity
receptor blocked by glivec
How do we use glevec and nilotonib?
in combination - if you use one then then the other you allow some to survive. Use in combo as no one drug will kill all
Who is Iressa more effective in>?
patients with mutation leading to hyperactive EGFR
patients with mutations in K ras won’t respond to EGFR inhibitors
Patient and tumour variability leads to…
variability in treatment response
How can PATIENT variability lead to different response fo therapy?
variations in drug metabolizing enzymes
e.g. TPMT can lead to chemotherapy toxicity
what is our aim in cancer treatments of the future
know more about the underlying causes/mutations so we can prognose and treat effectively
TEL-PDGFbeta receptor fusion is associated with what disease?
CMML - chronic myelomonocytotic leukaemia
What chromosomal changes canses TEL-PDGFbeta recptor fusion
translocation between chromosomes 5 and 12
amino terminal region of TEL (TF)
tyrosine kinase domain of PDGF receptor
What chromosomal changes cause TEL-PDGFbeta recptor fusion
translocation between chromosomes 5 and 12
amino terminal region of TEL (TF)
tyrosine kinase domain of PDGF receptor
What happens in TEL-PDGFbeta recptor fusion to cause cancer
kinase is always active (as the helix loop region of TEL induces oligomerisation)
in CMML what cells are affected
macrophages rather than neutrophils
how can we treat CMML
Glivec also inhibits TEL-PDGFbetaR activity`
Se of glivec
Weight gain
Bleeding and brushing
Signs of infection ( fever/chills)
what does STAT stands for
what activates it
signal transducers and activators of transcription
BCR-Abl
