Flashcards in Genetics of Chronic Myelogenous Leukemia (CML) Deck (26)
What is the oncogenic mechanism and treatment for CML?
-Genomic translocation t(9;22) creates new gene encoding constitutively active tyrosine kinase
-Targeted molecular therapy based on mechanism - tyrosine kinase inhibitors - Imantinib (Gleevac)
What are important things to remember about how CML develops?
-CML arises from defects in normal neutrophil differentiation pathway
-BCR-ABL genomic translocation = genetic basis for defects
-Fundamental defect in CML, BCR-ABL fusion protein = exploited to create therapy
What are the most abundant white cells in circulation?
What do we need to regulate proliferation of neutrophils?
-It's critical for fighting infection
-Generated continuously in the bone marrow
-Job of neutrophil lineage to generate neutrophils in a regulated fashion
What should you remember about stem cells?
-Pluripotent - capable of generating all lineages
-Capable of proliferation
What should you remember about progenitor cells?
-Capable of proliferation but not self renewal
-Multipotent - can generate more than one lineage
-Capacity becomes narrower as progresses down pathway
What should you remember about committed cells?
-Do not proliferate
-Only one fate, to generate the next step in the path to the neutrophil
Self renewal and proliferation are tightly regulated by. . .
. . .extracellular signaling from bone marrow!
How does differentiation of the neutrophil lineage occur?
-Bone marrow secretes factors specific for different lineages
-Factors bind receptors on progenitor cells
-SIgnal activates cell-type specific transcription factors
Ex: Progenitor cell - GMP
Cytokine - G-CSF
Transcription factor - CEBPalpha
Result - Neutrophil differentiation
What spurs the neutrophil lineage to go into CML chronic phase?
-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 is a constitutively active tyrosine kinase that activates proliferation and blocks apoptosis in absence of extracellular signals
-Mutation arises in hematopoietic stem cell but is passed down to all progeny
Expression fo BCR-ABL fusion protein from genomic translocation disrupts normal neutrophil differentiation.
What is special about BCR-ABL1 progenitor cells?
-Proliferate more than other cells, survive longer!
-Have more opportunity to acquire more mutations which can make cells more oncogenic
-DO NOT self renew
-Continue to differentiate
What is the CML chronic phase like?
-Expansion of progenitor and committed cells
-Mature cells still produced
-Disease relatively mild
-BCR-ABL1 translocation in hematopoietic stem cell --> Increased proliferation and survival of progenitor cells, opportunity to acquire more mutations
What is the blast phase like?
-GMP acquires ability tot self renew, acquires block to differentiation --> huge expansion of blasts, 30% extramedullary
What should you remember about CML accelerated and blast phases?
-BCR-ABL1 alone does not cause progression from chronic to blast phase
-Additional changes needed:
---GMP acquire self renewal capacity - Wnt beta cattiness signaling is activated
---Differentiation is blocked - translation of CEBPalpha is inhibited
What is the outcome of CML accelerated and blast phases?
-Extreme expansion of blasts
-Production of functional mature cells blocked
What is the mechanism of the BCR-ABL1 translocation?
-Double stranded breaks occur in two chromosomes at specific breakpoints
--Two most common:
---p210 in CML, most common
---p190 in some ALL, less common
--Why these sites is not understood
-Mechanism used is non-homologous end joining (NHEJ)
--Common DNA repair mechanisms
--Doesn't require extensive homology
-Ends of different chromosomes are joined
What is BCR?
-Key functional domain for normal protein - Ser/Thr kinase domain
-Key functional domains for oncogenic fusion protein coiled-coil domain tyrosine 177
-Normal function - role in inhibition of some inflammatory responses
What is ABL1?
-Key functional domain for both normal and oncogenic fusion protein is tyrosine kinase
-In normal protein, kinase is held inactive unless activated by external signals
-Long chain fatty acid myristate maintains inhibition
-Normal functions: role in DNA repair cytoskeletal organization
NEITHER BCR or ABL ALONE ARE ONCOGENIC!!
What is the difference between the ABL and BCR-ABL1 kinases?
ABL - require extracellular signaling - then protein opens up conformation and this makes it possible for the kinase to dimerize
BCR-ABL1 - dimerization can occur WITHOUT AN EXTRACELLULAR SIGNAL --> this causes phosphorylation of tyrosine 177 (occurs in CML cells)
ABL tyrosine kinase phosphorylates Y177 in CML. Phosphorylation causes:
-Protection against apoptosis
Is BCR a tyrosine kinase?
How is CML treated?
-Targeting it BCR-ABL fusion protein
-CML is treated with BCR-ABL specific tyrosine kinase inhibitors
-Most BCR-ABL mutated cells can be eliminated
-Transition to blast phase can be blocked
What is Imatinib?
-Prototype of BCR-ABL specific tyrosine kinase inhibitors
-It specifically inactivates ABL1 kinase by blocking ATP binding
-Prevents selective advantage that comes from activated oncogenic signaling pathways
-Inactivation of BCR-ABL in mutant cells also causes apoptosis (cells became dependent on BCR-ABL for proliferation and anti-apoptosis signaling)
-Loss of BCR-ABL mutant cells allows normal cells to repopulate
How effective is Imatinib?
-5 yr survival for individuals with newly diagnosed chronic phase CML, treated with tyrosine kinase inhibitors - 85-90%
Natural history of disease w/out treatment:
---Chronic phase lasts
If BCR-ABL translocation arises in HSC, why does leukemia arise in the neutrophil lineage?
Specific signaling opportunities created by BCR-ABL protein benefit neutrophil progenitor more than others
1. Some lymphocytic leukemias do arise from BCR-ABL translocation but he fusion is at a different site, so many initiate different signaling
2. In CML, a subset of B cells do carry the BCR-ABL translocation but are not leukemic