Flashcards in Scott-CML Module Deck (45):
What chromosomal translocation is associated w/ CML?
What is the oncogenic mechanism by which the translocation affects cells?
BCR-ABL translocation creates new gene encoding constitutively active TK
CML arises from defects in what pathway....
Neutrophil differentiation pathway
What are the three stages of neutrophil differentiation?
What are the characteristics of stem cells?
Undergo self renewal
pluripotent--> generate all ineages
capable of proliferation
What are the characteristics of progenitor cells?
Lymphoid, erythroid, monocyte lineage
Proliferation but NO self renewal
Multipotent--can generate more than one lineage
Capacity becomes narrower as progress down pathway
What are the characteristics of committed cells?
Only one fate to generate the next step in the path to the neutrophil.
CML distorts what 2 processes in the Neutrophil pathway?
What initiates differentiation?
extracellular signals in the bone marrow--> TFs in hematpoietic cells
*each stage has a specific set of TFs which determine its characteristics
What drives differentiation?
Sequential expression of TF
What drives proliferation?
extracellular signaling form BM and Immune system
What cells have the highest capacity for proliferation?
Self renewal and proliferation are tightly regulated by _________from ________ and leads to _______________.
appropriate number of mature neutrophils produced
What happens to the neutrophil lineage in CML?
All the regulation is thrown out the window and normal neutrophil differentiation is disrupted.
How does the BCR-ABL1 lead to proliferation and the blocking of apoptosis?
genetic chimera of parts of BCR gene and ABL1 gene>
BCR-ABL1 fusion protein= constitutively active TK>
activates proliferation and blocks apoptosis
Where does the translocation occur? is it passed down?
Arises in hematopoietic stem cell
Passed down to ALL progeny
What is the selective advantage for cells containing the BCR-ABL1 mutation?
1) proliferate more, survive longer
2) have the opportunity to acquire more mutations--> make cells more oncogenic
How does the BCR-ABL1 mutation relate to the ability to self renew and differentiate?
DO NOT self renew
DO continue to differentiate
What is the outcome of BCR-ABL1 mutation?
Expansion of progenitor and committed cells
Mature cells still produced
What happens in the chronic phase of CML?
Increased proliferation and survival of progenitor cells
Opportunity to acquire more mutations
What happens in the blast phase of CML?
GMP acquires the ability to self renew
Acquires block to differentiation
Huge expansion of blast--> 30% extramedullary
What is the outcome of accelerated CML w/ a blast phase?
EXTREME expansion of blasts
production of functional mature cells blocked
What causes progression from chronic to blast phase?
GMP acquired self renewal capability
GMP lose ability to differentiate
What is the mechanism of BCR-ABL1 translocation?
Double strand breaks occur in 2 chromosomes at specific break points
What are the two most common break points?
P210- found in CML most common
P190- found in some ALL, less common
What is the mechanism used for BCR-ABL1 translocation?
Non-homologous end joining
-common DNA repair mechanism
-doesn't require extensive homology
What is the common initiating defect in CML?
reciprocal chromosomal translocation t(9:22)
DNA is physically rearranged-->fusion protein w/ constitutive TK activity
What are the normal domains in the BCR gene?
Ser/THR kinase domain
Coiled-coil domain, tyrosisne 177
What are the normal functions of the BCR gene?
Inhibition of some inflammatory responses
What are the normal domains in ABL1?
tyrosine kinase held inactive unless activated by external signals by myristate
What are the normal functions of ABL1?
What are tyrosine kinases?
regulator molecules in INTRAcellular signaling pathways that stimulate proliferatoin
What are the main differences between normal ABL1 and BCR-ABL1?
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
What are the different structural changes made to form BCR-ABL1?
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
What is needed to initiate cell signaling in normal ABL cells?
Extracellular signaling is NECESSARY to initiate signaling by ABL1
ABL in inactive conf>
Extracellular signaling open conformation>
Initiation of signaling pathways
What is needed to activated BACR-ABL to initiate signaling?
NO external signaling
BCR-ABL has NO myristate>
always in open conf>
coiled-coil domain promotes dimerization>
Initiate cell signaling
Why is the role of Y177 different in the BCR-ABL fusion protein from the BCR protein?
Y177 is subject to tyrosine phosphorylation in the fusion protein but NOT In BCR b/c BCR is NOT a tyrosine kinase.
What does Stat5 do?
Binds to specific promoters to activate transcription of target genes that promote proliferation and impede apoptosis
What is the role of JAK STAT in normal neutrophil development?
Cytokines (GM-CSF) are secreted by bone marrow-->
bind to receptors on progenitor cells>
initiates signaling through Jak 2>
phosphorylates Stat 5 on tyrosine>
What is the activation of Stat 5 unique in CML cells? What does this do for cells?
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.
What does Imatinib do?
Inactivates ABL1 kinase by blocking ATP binding
What leads to apoptosis in BCR-ABL mutant cells?
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.
How does the BCR-ABL TK work?
Transferring P from ATP to substrate>
proliferation and block of apoptosis
How does Imantib effect survival rates?
5 year survival for pts newly diagnosed w/ chronic CMLA nd treated w/ TK inhibitors 85-90%
Normally 3-4 years