CML 1

Question 1

neoplasia

Answer 1

abnormal mass tissue:

1. exceed normal
2. independent of it
3. autonomous (persist despite stopping causative stim)

Question 2

autonomous growth caused by

Answer 2

heritable mutations

Question 3

monoclonality means

Answer 3

all tumor cells = direct descendants of single cell

Question 4

hematopoiesis is what? takes place where?

Answer 4

form blood cells in BM

Question 5

HSC (2)

Answer 5

HSC has capacity for self renewal (give rise to another HSC) & multipotent (give rise to all hematopoietic cell lineages)

Question 6

committed progenitors

Answer 6

proliferative, give rise to cells in 1/few hematopoietic lineages (NOT self-renewing/multipotent)

Question 7

differentiated cells

Answer 7

acquired attribs of mature, fxn’al blood/immune cells. released from BM into PB

Question 8

division bw hematopoietic lineages

Answer 8

lymphoid & myeloid cells

Question 9

CML ~diagnosed in

Answer 9

adults (but can occur any age)

Question 10

chronic phase CML is

Answer 10

~asymptomatic. excess myeloid cells of diff degrees of maturity in PB.

Question 11

chronic phase CML ~ lasts

Answer 11

3 or + yrs

Question 12

CML symptoms

Answer 12

fatigue, weight loss, low hb/rbc (anemia), night sweats, splenomegaly (heavy in abdomen)

Question 13

blast crisis

Answer 13

if untreated, CML always turns to AL (~fatal)

Question 14

CML patients have incr levels of

Answer 14

monocytes/macrophages, neutro, eosino, basophils, megakaryo & erythrocytes

Question 15

G banding technique recognizes

Answer 15

diff xsomes

Question 16

philadelphia xsome is? discovered by who

Answer 16

abnormally small version of xsome 22 thx to t(9;22). janet rowley

Question 17

diff bw somatic(not inherited) & germline(constitutional) xsomal translocation

Answer 17

some somatic mutations assoc w growth advantage

Question 18

abnormal xsome in CML results from

Answer 18

somatic xsomal translocation

Question 19

how to detect philly xsome

Answer 19

by cytogenetics in 95% CML cases (other 5 % need other techniques)

Question 20

how specific is philly xsome

Answer 20

specific to CML but also in few AL cases arising de novo (w/o preceding chronic phase CML)

Question 21

clonal expansion of what

Answer 21

hematopoietic progenitor cells w philly xsome

Question 22

BCR-ABL includes what domains

Answer 22

bcr - coiled coil domain

abl - kinase domain

Question 23

normal ABL protein fxn

Answer 23

highly regulated, non-receptor tyrosine kinase. fxns in signal transduction from cell surface to nucleus, where it affects regulation of gene transcrip

Question 24

BCR

Answer 24

break pt cluster region

Question 25

BCR-ABL leads to

Answer 25

deregulated growth signals, occur when no external signal

Question 26

activation site in ABL

Answer 26

bind ATP when phosphorylated

Question 27

oncogene

Answer 27

cancer inducing. encode oncoproteins. ex. BCR-ABL

Question 28

proto-oncogene

Answer 28

normal cellular gene, upon alteration by mutation, can acquire ability to fxn as oncogene. ex. BCR & ABL

Question 29

tumor suppressor gene

Answer 29

inactivation contrib to cancer develop. ex. TP53 gene encodes TS protein p53

Question 30

BCR-ABL oncoprotein

Answer 30

unregulated, oncogenic tyrosine kinase

Question 31

mechs assoc w deregulation of ABL kinase activity in BCR-ABL

Answer 31

1. loss of inhib domain from N term of wt ABL | 2. addition of homodimerization (coiled coil) domain provided by BCR

Question 32

deregulated BCR-ABL kinase activity contrib to

Answer 32

accum of myeloid cells in BM & PB, conveying signals to cell nucleus to stim prolif & survival

Question 33

gleevec aka?

Answer 33

imatinib mesylate / STI 571

Question 34

imatinib binds to what

Answer 34

catalytic site of ABL / BCR-ABL to block kinase activity

Question 35

imatinib treatment leads to

Answer 35

withdrawing growth advantage, cell cycle arrest & apoptosis so normal cells repop

Question 36

transforming mutations turn HSC into

Answer 36

leukemic SC which give rise to bulk leukemic cells

Question 37

what cells can initiate tumor growth

Answer 37

LSC (need to target these) NOT bulk leukemic stem clls

Question 38

philly xsome +ve cells can repopulate in blood when?

Answer 38

on gleevec withdrawal, even after prolonged treatment since ~resistant to treatment

Question 39

in chronic phase CML, most myeloid & some lymphoid are philly xsome positive, meaning

Answer 39

translocation must have occurred in HSC

Question 40

philly xsome +ve HSC aka?

Answer 40

LSC

Question 41

how can BCR-ABL protein be resistant to gleevec?

Answer 41

CML cells develop mutations in BCR-ABL gene (selective advantage, become prevalent)

Question 42

gleevec does what

Answer 42

antagonize catalytic (tyrosine kinase) fxn of ABL or BCR-ABL

Question 43

is gleevec selective

Answer 43

very selective, target only a few TK's in addition to ABL

Question 44

gleevec is what kind of thereapy

Answer 44

targeted cancer therapy

Question 45

gleevec has adverse effects or not

Answer 45

very few

Question 46

effectiveness of gleevec

Answer 46

yes. decr BM cells w philly xsome & rate of progression to blast crisis (chronic to acute phase)

Question 47

is gleevec a cure for CML

Answer 47

NO cause it has little effect on philly xsome +ve LSC

Question 48

clones of CML cells may develop imatinib resistance by

Answer 48

missense (single AA) mutations in BCR-ABL to prevent binding & incr expression of BCR-ABL thru gene amp

Question 49

new tyrosine kinase inhibitors may be useful in imatinib resistant cases like

Answer 49

desatinib, nilotinib

Question 50

key to monitor treatment effect on CML cells in each patient since

Answer 50

imatinib not effective for everyone, imatinib resistance inducing mutations may occur. also TK inhibitors are available