CML Genetics

Question 1

Just for shits and giggles…what’s the genetic abnormlaity in CML again?

Answer 1

translocation of 9 and 22
the new chromosome 9 doesn’t do much, but the 22 is called the philadelphia chromosome and has the BCR-ABL fusion protein as a product, which a constitutively active tyrosine kinase

Question 2

WHat white blood cell in particular is affected in CML?

Answer 2

neutrophil

Question 3

Although the BCR-ABL mutation convers the ability to proliferate and survive longer, what does it NOT confer?

Answer 3

the ability to self renew - they still differentiate and act as functional, mature neutrophils

Question 4

Why is disease relatively mild in the chronic stage?

Answer 4

Because the neutrphils being produced can’t self renew and they’re mature cells

Question 5

What does the CML need in order to enter the accelerated and blast phases?

Answer 5

more mutations - often WNT and beta-catenin signaling

Question 6

WHy is accelerated phase worse than chronic phase?

Answer 6

Because the new mutation allow the granulocyte macrophage progenitor to SELF RENEW and they LOSE the ability to differentiate

Question 7

What’s the most common breakpoint in the CML mutation?

Answer 7

p210

Question 8

What’s the mechanism for joining the two chrosomsomes?

Answer 8

nonhomologous end joining (it’s a common DNA repair mechanism that doesn’t require homology - you just squish the two ends together)

Question 9

What’s the normal function of BCR?

Answer 9

it’s the key functional domain for a normal protien Ser/Thr kinase domain

has a role in inhibition of some inflammatory responses

Question 10

WHat’s the function of normal ABL1?

Answer 10

it’s a tyroskine kinase that’s normally held inactive unless activated by extternal signals

role in DNA repair and cytoskeleton reorganization

Question 11

What long hcain fatty acid maintains the inhibition of the ABL1 tyrosine kinase under normal conditions?

Answer 11

myristate

Question 12

WHat’s the key function for the mutated BCR on BCR-ABL?

Answer 12

It has a coiled-coil domain (which promotes the dimerization necessary for the cosntant activation of the BCR-ABL tyrosine kinase)

Question 13

What’s lost in BCR_ABL that allows the constant activation?

Answer 13

the inhibition from myristate

Question 14

What’s phosphorylated on the BCR portion to create a new binding site for intracellular signaling proteins?

Answer 14

tyrosine 177

Question 15

Why does tyrosine 177 not get phosphorylated in the normal BCR?

Answer 15

because BCR isn’t a tyrosine kinase

Question 16

What signaling pathway in particular is activated by the dimerized BCR_ABL tyrosine kinase?

Answer 16

the Jak2-Stat5 signaling pathway (it means it can work without signals from GM0CSF)

Question 17

THer eare three other signaling pathways affected….

Answer 17

GRB2 group of adapters
RAS-MAPK
PI3 kinase pathway

Question 18

What’s the prototype drug that blocks teh BCR_ABL tyrosine kinase?

Answer 18

imatinib

Question 19

WHat does inactivation of BCR_ABL cause?

Answer 19

apoptosis - the malignant cells have come to rely on it for proliferation

Question 20

What are the limitations of imatinib?

Answer 20

many can develop secondary resistance primarily due to mutations in BCR_ABL

THey’re not effective against blast phase disease (because there are additional mutations that make the cells independent of BCR-ABL)

CML STEM CELLS are resistant to tyrosine kinase inhibitors - and those are the ones we really want to kill - so these drugs have to be taken for life