CML Module - Scott

Question 1

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

Answer 1

• 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

Question 2

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

Answer 2

• 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

Question 3

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

Answer 3

• 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)

Question 4

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

Answer 4

• 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

Question 5

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

Answer 5

• 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

Question 6

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

Answer 6

• 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

Question 7

What is the mechanism by which imatinib blocks CML progression?

Answer 7

• 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

Question 8

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

Answer 8

• 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!