CML Module - Scott Flashcards

1
Q

How is the treatment of CML an example of successful molecular medicine?

A
  • Initiating event of CML known at molecular level
    • chromosomal translocation t(9;22)
  • Oncogenic mechanism known
    • genomic translocation creates new gene encoding constitutively active tyrosine kinase
  • Targeted molecular therapy based on mechanism
    • tyrosine kinase inhibitors = Imantinib
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are the genetic changes underlying the development and progression of CML?

A
  • BCR-ABL1 genomic translocation in hematopoietic stem cell
    • creates genetic chimera of parts of BCR (Breakpoint Cluster Region) gene and ABL1 (Ableson tyrosine kinase) gene
    • BCR-ABL1 = fusion protein that is a constitutively active tyrosine kinase
      • activates proliferation
      • blocks apoptosis
    • Mutation arises in hematopoietic stem cell, but is passed down to ALL PROGENY
      • selective advantage
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the characteristics of the neutrophil lineage in a normal patient?

A
  • Proliferation is primarily during progenitor stages
    • Occurs in response to extracellular signaling
      • bone marrow stromal cells
      • immune response signaling
  • Bone marrow secretes factors for different lineages to differentiate
    • Factors bind to receptors on progenitor cells
    • signal activates cell-type specific transcription factors

(GMP → G-CSF → txn CEBP-alpha → neutrophil)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the characteristics of the neutrophil lineage in the chronic phase of CML?

A
  • BCR-ABL1 tyrosine kinase → selective advantage
    • progenitor cells proliferate more, survive longer
    • progenitor cells have the opportunity to acquire more mutations which can make cells more oncogenic
    • DOES NOT confer ability to self-renew
  • Mature cells are still produced
  • Disease is relatively mild
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are the characteristics of the neutrophil lineage in the accelerated/blast phases of CML?

A
  • Granulocyte Macrophage Progenitor acquires:
    • block to differentiation
    • ability to self renew
  • Results in huge expansion of blasts (30% extramedullary)
  • Production of functional mature cells is blocked
  • Severe disease
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the mechanisms by which BCR-ABL fusion protein promotes deregulated proliferation?

A
  • No cell signaling needed to activate BCR-ABL1
    • coiled-coil domain is added from BCR → promotes dimerization → dimer necessary for activation
    • myristate attachment site lost from ABL1 → removal of key inhibitory pathway
  • Constitutively active tyrosine kinase
    • no external cell signalling needed
    • Y177 is readily subject to tyrosine kinase phosphorylation
      • starting point for several oncogenic signaling pathway
  • Constitutive activation of Stat5 independent of external signaling
    • no cytokine needed
    • BCR-ABL readily activates JAK
    • JAK activates Stat5 → transcription, proliferation, anti-apoptosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the mechanism by which imatinib blocks CML progression?

A
  • Imatinib = BCR-ABL specific tyrosine kinase inhibitor
    • specifically inactivates ABL1 kinase by blocking ATP binding
    • prevents the selective advantage that comes from activated oncogenic signaling pathways
    • causes apoptosis (lose anti-apoptosis signaling w/o BCR-ABL)
    • Loss of BCR-ABL mutant cells allows normal cells to repopulate
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are the three main limitations of Imatinib treatment of CML?

A
  • Many develop secondary resistance to Imatinib primarily due to mutation in BCR-ABL
  • BCR-ABL1 tyrosine kinase inhibitors are not effective against blast phase disease
  • CML stem cells are resistant to tyrosine kinase inhibitors
    • Imatinib must be taken for life!
How well did you know this?
1
Not at all
2
3
4
5
Perfectly