CE L6 Leukeamias

Question 1

L is cancer of what cell?

Answer 1

WBC

Question 2

Why is CML the best understood?

Answer 2

Easy to obtain samples

Question 3

What leads to death in CML

Answer 3

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

Question 4

What do CML WBC looklike

Answer 4

immature and blast like

Question 5

What does a blood sample from CML look like

Answer 5

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

Question 6

What are the three branches haemopoetic cells become?

Answer 6

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

Question 7

How is L clasified

Answer 7

acute or chronic

depending on cell of origin (myeloid or lymphoid)

Question 8

Is chronic or acute L worse?

Answer 8

acute

chronic is slower growing so more time to treat

Question 9

Symptoms (5)

Answer 9

• 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

Question 10

Stages of CML

Answer 10

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

Question 11

What is blase crisis?

Answer 11

no functional WBC

Question 12

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

Answer 12

Ras

Question 13

4 Common chromosomal abnormalities in L

Answer 13

addition
translocation (Larger changes)
deletion
amplification

Gross chromosomal changes are a specific feature of L

Question 14

Studying leukemias revealed ………………. oncogenes

Answer 14

novel - genes that dont exist in normal patietns

Question 15

95% of CML has what chromosomal feature

Answer 15

reciprocal translocation between chromosomes 9 and 22

Question 16

95% of CML has what chromosomal feature

Answer 16

reciprocal translocation between chromosomes 9 and 22

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

Question 17

What is the name of the novel oncogene from reciprical transformation

Answer 17

BCR-ABL

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

Question 18

another name for the BCR-ABL chromosone

Answer 18

philidelphia chromosome - diagnostic marker

Question 19

What is Abl like in normal cells vs CML

Answer 19

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

Question 20

What is the result of active Abl (3)

Answer 20

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

Question 21

Theory about BCR-Abls role in CML

Answer 21

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

Question 22

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

Answer 22

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

Question 23

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

Answer 23

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

Question 24

Where is C-Abl found

role of each?

Answer 24

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

Question 25

What is C-Abl activated by

Answer 25

DNA damage S phase downstream of intergrin signalling

Question 26

what is C-abl

Answer 26

non-receptor protein tyrosine kinase

Question 27

What type of molecule is gleevec?

Answer 27

small synthetic molecule (imatinib mesylate)

Question 28

How does Glivec work

Answer 28

inhibits proliferation by.... blocking Abl tyrosine kinase, PDGFbetaR and c-kit tyrosine kinase

Question 29

what is the advantage of Glivec?

Answer 29

relatively few s/e

Question 30

2 causes of resistance to glivec:

Answer 30

-BCR-Abl amplification

Question 31

2 causes of resistance to glivec:

Answer 31

- 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)

Question 32

How long is treatment with Glivec?

Answer 32

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

Question 33

how does resistance develop?

Answer 33

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

Question 34

What is Dasatinib/nilotinib

Answer 34

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

Question 35

What was the issue with 3rd gen BCR abl inhibitors

Answer 35

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

Question 36

How can we use gliver for gastrointestinal tumours?

Answer 36

s

Question 37

How can we use glivec for gastrointestinal tumours?

Answer 37

tumour is driven by constitutive c-kit recptor activity receptor blocked by glivec

Question 38

How do we use glevec and nilotonib?

Answer 38

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

Question 39

Who is Iressa more effective in>?

Answer 39

patients with mutation leading to hyperactive EGFR | patients with mutations in K ras won't respond to EGFR inhibitors

Question 40

Patient and tumour variability leads to...

Answer 40

variability in treatment response

Question 41

How can PATIENT variability lead to different response fo therapy?

Answer 41

variations in drug metabolizing enzymes e.g. TPMT can lead to chemotherapy toxicity

Question 42

what is our aim in cancer treatments of the future

Answer 42

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

Question 43

TEL-PDGFbeta receptor fusion is associated with what disease?

Answer 43

CMML - chronic myelomonocytotic leukaemia

Question 44

What chromosomal changes canses TEL-PDGFbeta recptor fusion

Answer 44

translocation between chromosomes 5 and 12 amino terminal region of TEL (TF) tyrosine kinase domain of PDGF receptor

Question 45

What chromosomal changes cause TEL-PDGFbeta recptor fusion

Answer 45

translocation between chromosomes 5 and 12 amino terminal region of TEL (TF) tyrosine kinase domain of PDGF receptor

Question 46

What happens in TEL-PDGFbeta recptor fusion to cause cancer

Answer 46

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

Question 47

in CMML what cells are affected

Answer 47

macrophages rather than neutrophils

Question 48

how can we treat CMML

Answer 48

Glivec also inhibits TEL-PDGFbetaR activity`

Question 49

Se of glivec

Answer 49

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

Question 50

what does STAT stands for | what activates it

Answer 50

signal transducers and activators of transcription BCR-Abl