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IHO Week 4 > Scott-CML Module > Flashcards

Scott-CML Module Flashcards

1
Q

What chromosomal translocation is associated w/ CML?

A

t (9;22)

Philadelphia chromosome

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2
Q

What is the oncogenic mechanism by which the translocation affects cells?

A

BCR-ABL translocation creates new gene encoding constitutively active TK

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3
Q

CML arises from defects in what pathway….

A

Neutrophil differentiation pathway

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4
Q

What are the three stages of neutrophil differentiation?

A

Stem cells
Progenitor cells
Committed cells

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5
Q

What are the characteristics of stem cells?

A

Undergo self renewal
pluripotent–> generate all ineages
capable of proliferation

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6
Q

What are the characteristics of progenitor cells?

A

Lymphoid, erythroid, monocyte lineage

Proliferation but NO self renewal
Multipotent–can generate more than one lineage
Capacity becomes narrower as progress down pathway

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7
Q

What are the characteristics of committed cells?

A

Myeloblast–> Neutrophil

Don’t proliferate
Only one fate to generate the next step in the path to the neutrophil.

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8
Q

CML distorts what 2 processes in the Neutrophil pathway?

A

Differentiation

proliferation

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9
Q

What initiates differentiation?

A

extracellular signals in the bone marrow–> TFs in hematpoietic cells

*each stage has a specific set of TFs which determine its characteristics

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10
Q

What drives differentiation?

A

Sequential expression of TF

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11
Q

What drives proliferation?

A

extracellular signaling form BM and Immune system

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12
Q

What cells have the highest capacity for proliferation?

A

progenitor cells

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13
Q

Self renewal and proliferation are tightly regulated by _________from ________ and leads to _______________.

A

extracellular signaling
bone marrow
appropriate number of mature neutrophils produced

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14
Q

What happens to the neutrophil lineage in CML?

A

All the regulation is thrown out the window and normal neutrophil differentiation is disrupted.

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15
Q

How does the BCR-ABL1 lead to proliferation and the blocking of apoptosis?

A

BCR-ABL1>
genetic chimera of parts of BCR gene and ABL1 gene>
BCR-ABL1 fusion protein= constitutively active TK>
activates proliferation and blocks apoptosis

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16
Q

Where does the translocation occur? is it passed down?

A

Arises in hematopoietic stem cell

Passed down to ALL progeny

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17
Q

What is the selective advantage for cells containing the BCR-ABL1 mutation?

A

Progenitor cells:

1) proliferate more, survive longer
2) have the opportunity to acquire more mutations–> make cells more oncogenic

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18
Q

How does the BCR-ABL1 mutation relate to the ability to self renew and differentiate?

A

Progenitor cells
DO NOT self renew
DO continue to differentiate

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19
Q

What is the outcome of BCR-ABL1 mutation?

A

Expansion of progenitor and committed cells

Mature cells still produced

20
Q

What happens in the chronic phase of CML?

A

Increased proliferation and survival of progenitor cells

Opportunity to acquire more mutations

21
Q

What happens in the blast phase of CML?

A

GMP acquires the ability to self renew
Acquires block to differentiation

Huge expansion of blast–> 30% extramedullary

22
Q

What is the outcome of accelerated CML w/ a blast phase?

A

EXTREME expansion of blasts
production of functional mature cells blocked
severe disease

23
Q

What causes progression from chronic to blast phase?

A

Additional mutations
GMP acquired self renewal capability
GMP lose ability to differentiate

24
Q

What is the mechanism of BCR-ABL1 translocation?

A

Double strand breaks occur in 2 chromosomes at specific break points

25
Q

What are the two most common break points?

A

P210- found in CML most common

P190- found in some ALL, less common

26
Q

What is the mechanism used for BCR-ABL1 translocation?

A

Non-homologous end joining

  • common DNA repair mechanism
  • doesn’t require extensive homology
27
Q

What is the common initiating defect in CML?

A

reciprocal chromosomal translocation t(9:22)

DNA is physically rearranged–>fusion protein w/ constitutive TK activity

28
Q

What are the normal domains in the BCR gene?

A

Ser/THR kinase domain

Coiled-coil domain, tyrosisne 177

29
Q

What are the normal functions of the BCR gene?

A

Inhibition of some inflammatory responses

30
Q

What are the normal domains in ABL1?

A

tyrosine kinase held inactive unless activated by external signals by myristate

31
Q

What are the normal functions of ABL1?

A

DNA repair

cytoskeletal organization

32
Q

What are tyrosine kinases?

A

regulator molecules in INTRAcellular signaling pathways that stimulate proliferatoin

33
Q

What are the main differences between normal ABL1 and BCR-ABL1?

A

ABL1 in normal cells is inactivated unless activated by intracellular signaling.
BCR-ABL1 in CML cells is constitutively active.

ABL1 and BCR-ABL1 activate different intracellular signaling pathways

34
Q

What are the different structural changes made to form BCR-ABL1?

A
  1. coiled-coil domain is added from BCR–> dimerization necessary for activation
  2. Myristate attachement site lost form ABL1–>Necessary for autoinhibition of ABL1 TK activity
  3. Tyrosine-177- added from BCR phosphorylation of y-177 to create a new binding site for intracellular signaling proteins
35
Q

What is needed to initiate cell signaling in normal ABL cells?

A

Extracellular signaling is NECESSARY to initiate signaling by ABL1

ABL in inactive conf>
myristate inhibits>
Extracellular signaling open conformation>
dimerization>
TK transphosphorylation>
Initiation of signaling pathways
36
Q

What is needed to activated BACR-ABL to initiate signaling?

A

NO external signaling

BCR-ABL has NO myristate>
always in open conf>
coiled-coil domain promotes dimerization>
TK active>
Initiate cell signaling
37
Q

Why is the role of Y177 different in the BCR-ABL fusion protein from the BCR protein?

A

Y177 is subject to tyrosine phosphorylation in the fusion protein but NOT In BCR b/c BCR is NOT a tyrosine kinase.

38
Q

What does Stat5 do?

A

Binds to specific promoters to activate transcription of target genes that promote proliferation and impede apoptosis

39
Q

What is the role of JAK STAT in normal neutrophil development?

A 
Cytokines (GM-CSF) are secreted by bone marrow-->
bind to receptors on progenitor cells>
initiates signaling through Jak 2>
phosphorylates Stat 5 on tyrosine>
activates it
40
Q

What is the activation of Stat 5 unique in CML cells? What does this do for cells?

A

BCR-ABL1 kinase activates Stat5 INDEPENDENTLY of external signals>
trxn of proliferation factors and anti-apoptotic factors are downregulated

This gives selective advantage to cells carrying this mutation so they can proliferate and create MORE mutations. Boooo.

41
Q

What does Imatinib do?

A

Inactivates ABL1 kinase by blocking ATP binding

42
Q

What leads to apoptosis in BCR-ABL mutant cells?

A

BCR-ABL mutant cells are dependent on BCR-ABL for proliferation and anti-apoptosis signaling.

When BCR-ABL gets inactivated those cells are shit out of luck and it leads to APOPTOSIS. Loss of BCR-ABL mutatnt cells allows normal cells to repopulate.

43
Q

How does the BCR-ABL TK work?

A

Binding ATP>
Transferring P from ATP to substrate>
proliferation and block of apoptosis

44
Q

How does Imantib effect survival rates?

A

5 year survival for pts newly diagnosed w/ chronic CMLA nd treated w/ TK inhibitors 85-90%

Normally 3-4 years

45
Q

What are the limitations of Imantib?

A
  1. Secondary resistand d/t mut in BCR-ABL
  2. NOT effective against blast phase disease
  3. CML stem cells are resistant to TK inhibitors

IHO Week 4 (15 decks)

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