CML 1 Flashcards
neoplasia
abnormal mass tissue:
- exceed normal
- independent of it
- autonomous (persist despite stopping causative stim)
autonomous growth caused by
heritable mutations
monoclonality means
all tumor cells = direct descendants of single cell
hematopoiesis is what? takes place where?
form blood cells in BM
HSC (2)
HSC has capacity for self renewal (give rise to another HSC) & multipotent (give rise to all hematopoietic cell lineages)
committed progenitors
proliferative, give rise to cells in 1/few hematopoietic lineages (NOT self-renewing/multipotent)
differentiated cells
acquired attribs of mature, fxn’al blood/immune cells. released from BM into PB
division bw hematopoietic lineages
lymphoid & myeloid cells
CML ~diagnosed in
adults (but can occur any age)
chronic phase CML is
~asymptomatic. excess myeloid cells of diff degrees of maturity in PB.
chronic phase CML ~ lasts
3 or + yrs
CML symptoms
fatigue, weight loss, low hb/rbc (anemia), night sweats, splenomegaly (heavy in abdomen)
blast crisis
if untreated, CML always turns to AL (~fatal)
CML patients have incr levels of
monocytes/macrophages, neutro, eosino, basophils, megakaryo & erythrocytes
G banding technique recognizes
diff xsomes
philadelphia xsome is? discovered by who
abnormally small version of xsome 22 thx to t(9;22). janet rowley
diff bw somatic(not inherited) & germline(constitutional) xsomal translocation
some somatic mutations assoc w growth advantage
abnormal xsome in CML results from
somatic xsomal translocation
how to detect philly xsome
by cytogenetics in 95% CML cases (other 5 % need other techniques)
how specific is philly xsome
specific to CML but also in few AL cases arising de novo (w/o preceding chronic phase CML)
clonal expansion of what
hematopoietic progenitor cells w philly xsome
BCR-ABL includes what domains
bcr - coiled coil domain
abl - kinase domain
normal ABL protein fxn
highly regulated, non-receptor tyrosine kinase. fxns in signal transduction from cell surface to nucleus, where it affects regulation of gene transcrip
BCR
break pt cluster region
BCR-ABL leads to
deregulated growth signals, occur when no external signal
activation site in ABL
bind ATP when phosphorylated
oncogene
cancer inducing. encode oncoproteins. ex. BCR-ABL
proto-oncogene
normal cellular gene, upon alteration by mutation, can acquire ability to fxn as oncogene. ex. BCR & ABL
tumor suppressor gene
inactivation contrib to cancer develop. ex. TP53 gene encodes TS protein p53
BCR-ABL oncoprotein
unregulated, oncogenic tyrosine kinase
mechs assoc w deregulation of ABL kinase activity in BCR-ABL
- loss of inhib domain from N term of wt ABL
2. addition of homodimerization (coiled coil) domain provided by BCR
deregulated BCR-ABL kinase activity contrib to
accum of myeloid cells in BM & PB, conveying signals to cell nucleus to stim prolif & survival
gleevec aka?
imatinib mesylate / STI 571
imatinib binds to what
catalytic site of ABL / BCR-ABL to block kinase activity
imatinib treatment leads to
withdrawing growth advantage, cell cycle arrest & apoptosis so normal cells repop
transforming mutations turn HSC into
leukemic SC which give rise to bulk leukemic cells
what cells can initiate tumor growth
LSC (need to target these) NOT bulk leukemic stem clls
philly xsome +ve cells can repopulate in blood when?
on gleevec withdrawal, even after prolonged treatment since ~resistant to treatment
in chronic phase CML, most myeloid & some lymphoid are philly xsome positive, meaning
translocation must have occurred in HSC
philly xsome +ve HSC aka?
LSC
how can BCR-ABL protein be resistant to gleevec?
CML cells develop mutations in BCR-ABL gene (selective advantage, become prevalent)
gleevec does what
antagonize catalytic (tyrosine kinase) fxn of ABL or BCR-ABL
is gleevec selective
very selective, target only a few TK’s in addition to ABL
gleevec is what kind of thereapy
targeted cancer therapy
gleevec has adverse effects or not
very few
effectiveness of gleevec
yes. decr BM cells w philly xsome & rate of progression to blast crisis (chronic to acute phase)
is gleevec a cure for CML
NO cause it has little effect on philly xsome +ve LSC
clones of CML cells may develop imatinib resistance by
missense (single AA) mutations in BCR-ABL to prevent binding & incr expression of BCR-ABL thru gene amp
new tyrosine kinase inhibitors may be useful in imatinib resistant cases like
desatinib, nilotinib
key to monitor treatment effect on CML cells in each patient since
imatinib not effective for everyone, imatinib resistance inducing mutations may occur. also TK inhibitors are available
