Chronic myeloid leukemia Flashcards
WBCs
produce granulocytes
HSC
hematopoietic stem cells
- produce progenitor cells
- self renewing
progenitor cells (2)
- non self renewing
Myeloid and lymphoid stem cells
Myeloid:
produces rbc platelets and granulocytes
chronic myeloid leukemia
- unregulated and increase in myeloid cells in bone marrow
- accumulate in the blood
- no early symptoms,
- blood test: increased WBCs
- gradual development
Outcomes: bruise easily
less platelets
Outcomes: frequent infections
- immature WBCs not commited to role
Outcomes: bone pain
- rapid dividing myeloid stem cells
CML: triphasic disease
1) stable/chronic phase: excess differentiated WBCs, no sypmtoms
2) accelerated phase: malignant cell loses ability to diferentiate, many more
3) Blast crisis: large increase in immature myeloid cells
- death 4-6 years if diagnosed at this stage
Philidelphia chromosome
reciprocal translocation leads to fusion protein
- somatic translocation (not germ lines)
chromo9: BCR
Chromo22: Abl1
-BCR-Abl code this fusion protein
- use ATP to phosphorylate other proteins
-always on
BCR
breakpoint cluster region
- serine or threorine phosphorylation
Abl1
abelson murine leukemia viral oncogene homolog
- phosphorylates tyrosine (kinase)
- involved in cell division and differentiation
- negatively regulated by SH3 domain
pathogenesis of CML
- Due to no SH3 domain, always on
- elevated tyrosine kinase activity
- bind to subtrate and use ATP to phosphorylate tyrosine
- activate transcription factor STAT5, normally a monomer to be dimerizing
- translocate into nucleus
- cell growth/proliferation without apoptosis and differentiation
why is bcr-abl good as a drug target
only located in CML cells so specific, minimizes damage
open conformer
- ATP free to bind and activate
