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Cancer CE & VP > CE L6 Leukeamias > Flashcards

CE L6 Leukeamias Flashcards

1
Q

L is cancer of what cell?

A

WBC

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2
Q

Why is CML the best understood?

A

Easy to obtain samples

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3
Q

What leads to death in CML

A

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

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4
Q

What do CML WBC looklike

A

immature and blast like

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5
Q

What does a blood sample from CML look like

A

Normally we have 5% WBC but there is much more in L

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6
Q

What are the three branches haemopoetic cells become?

A

Myeloid (inate immune)
Erythoid (RBC)
Lymphoid (adaptive immune) - t and b cells

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7
Q

How is L clasified

A

acute or chronic

depending on cell of origin (myeloid or lymphoid)

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8
Q

Is chronic or acute L worse?

A

acute

chronic is slower growing so more time to treat

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9
Q

Symptoms (5)

A
  • 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
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10
Q

Stages of CML

A
  1. initial chronic
  2. Accelerated phase after 4 years
  3. Acute - blast crisis
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11
Q

What is blase crisis?

A

no functional WBC

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12
Q

What is mutated in over 50% of acute myeloid leukemias?

A

Ras

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13
Q

4 Common chromosomal abnormalities in L

A

addition
translocation (Larger changes)
deletion
amplification

Gross chromosomal changes are a specific feature of L

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14
Q

Studying leukemias revealed ………………. oncogenes

A

novel - genes that dont exist in normal patietns

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15
Q

95% of CML has what chromosomal feature

A

reciprocal translocation between chromosomes 9 and 22

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16
Q

95% of CML has what chromosomal feature

A

reciprocal translocation between chromosomes 9 and 22

- takes just part of the gene so a novel oncogene is formed

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17
Q

What is the name of the novel oncogene from reciprical transformation

A

BCR-ABL

takes the break point cluster region (BCR) and Abl tyrosine kinase

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18
Q

another name for the BCR-ABL chromosone

A

philidelphia chromosome - diagnostic marker

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19
Q

What is Abl like in normal cells vs CML

A

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

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20
Q

What is the result of active Abl (3)

A

Constitutively activates:
Ras pathway
Phosphoinositide-3-kinase pathway
Signal tranducers are activators of transcription (STATs)

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21
Q

Theory about BCR-Abls role in CML

A

this is initial mutation making it unstable so driving accumulation of further mutations

22
Q

Why can’t we used mabs to target BCR-Abl?

A

it’s cytoplasmic - not a receptor so we can’t target with Ab as it’s in the cell and they are too big

23
Q

Why can’t we used mabs to target BCR-Abl?

A

it’s cytoplasmic - not a receptor so we can’t target with Ab as it’s in the cell and they are too big

24
Q

Where is C-Abl found

role of each?

A

cytoplasmic and nuclear location
nuclear - interacts with p53 and Rb to regulate gene transcription
cytomplasmic - role in cell growth

25
Q

What is C-Abl activated by

A

DNA damage
S phase
downstream of intergrin signalling

26
Q

what is C-abl

A

non-receptor protein tyrosine kinase

27
Q

What type of molecule is gleevec?

A

small synthetic molecule (imatinib mesylate)

28
Q

How does Glivec work

A

inhibits proliferation by….

blocking Abl tyrosine kinase, PDGFbetaR and c-kit tyrosine kinase

29
Q

what is the advantage of Glivec?

A

relatively few s/e

30
Q

2 causes of resistance to glivec:

A

-BCR-Abl amplification

31
Q

2 causes of resistance to glivec:

A
  • 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)
32
Q

How long is treatment with Glivec?

A

lifelong - if you leave once cell behind it could come back

33
Q

how does resistance develop?

A

initial drug treatment may select for resistance or resistant clones may exist from the start

34
Q

What is Dasatinib/nilotinib

A

2nd generation CML therapies - bind to active confirmation of BCR-abl and can therefore be effective when point mutation has led to glivec resistance

35
Q

What was the issue with 3rd gen BCR abl inhibitors

A

there was another mutation so a third gen inhibitor was made against this however it was too cardiotoxic

36
Q

How can we use gliver for gastrointestinal tumours?

A

s

37
Q

How can we use glivec for gastrointestinal tumours?

A

tumour is driven by constitutive c-kit recptor activity

receptor blocked by glivec

38
Q

How do we use glevec and nilotonib?

A

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

39
Q

Who is Iressa more effective in>?

A

patients with mutation leading to hyperactive EGFR

patients with mutations in K ras won’t respond to EGFR inhibitors

40
Q

Patient and tumour variability leads to…

A

variability in treatment response

41
Q

How can PATIENT variability lead to different response fo therapy?

A

variations in drug metabolizing enzymes

e.g. TPMT can lead to chemotherapy toxicity

42
Q

what is our aim in cancer treatments of the future

A

know more about the underlying causes/mutations so we can prognose and treat effectively

43
Q

TEL-PDGFbeta receptor fusion is associated with what disease?

A

CMML - chronic myelomonocytotic leukaemia

44
Q

What chromosomal changes canses TEL-PDGFbeta recptor fusion

A

translocation between chromosomes 5 and 12

amino terminal region of TEL (TF)
tyrosine kinase domain of PDGF receptor

45
Q

What chromosomal changes cause TEL-PDGFbeta recptor fusion

A

translocation between chromosomes 5 and 12

amino terminal region of TEL (TF)
tyrosine kinase domain of PDGF receptor

46
Q

What happens in TEL-PDGFbeta recptor fusion to cause cancer

A

kinase is always active (as the helix loop region of TEL induces oligomerisation)

47
Q

in CMML what cells are affected

A

macrophages rather than neutrophils

48
Q

how can we treat CMML

A

Glivec also inhibits TEL-PDGFbetaR activity`

49
Q

Se of glivec

A

Weight gain
Bleeding and brushing
Signs of infection ( fever/chills)

50
Q

what does STAT stands for

what activates it

A

signal transducers and activators of transcription

BCR-Abl

Cancer CE & VP (15 decks)

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