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AL 1 Flashcards

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1
Q

stem cells characterized by 2 things

A

self-renewal (rare. SC ~quiescent) & multipotent (give rise to progeny thru successive differentiation steps, to mature cells)

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2
Q

HSC found in?

A

BM, cord blood, less in peripheral blood

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3
Q

HSC are what kind of cells & do what?

A

long lived, give rise to all blood cells

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4
Q

HSC in how many BM cells? per person?

A

HSC are RARE. comprise ~1 per 10^8 BM cells. 11k-22k.

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5
Q

normal hematopoiesis is

A

polyclonal

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6
Q

HSC contrib to prod ? new blood cells each day

A

10^11 -12

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7
Q

hematopoiesis is when HSC make…

A

mature blood cells

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8
Q

where does hematopoiesis ~occur in adults?

A

BM

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9
Q

myeloid cells

A

monocytes>macrophages, eosino, baso, neutrophils

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10
Q

lymphoid cells

A

NK cell, T, B lymphocytes

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11
Q

AL vs CL: cells & chromatin

A

AL - immature cells, more open nuclear chromatin. CL - mature, clumped

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12
Q

AL vs CL: progress

A

AL - rapid, CL - slow

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13
Q

AL vs CL: treatment

A

AL - need immediately. CL - monitor some time before treat

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14
Q

AL vs CL: characterization of hematopoietic cancer

A

AL - proliferation of immature cells. CL - mature.

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15
Q

leukemia 4 main types

A

ALL lymphoblastic, CLL lymphocytic, AML myeloid, CML myelogenous

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16
Q

leukemias disrupt hematopoiesis. polyclonal turns to

A

monoclonal

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17
Q

blasts

A

HSC, common myeloid, lymphoid progenitors

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18
Q

CLL / CML

A

incr in B lymphocytes mostly / baso, neutro, eosinophils, monocytes

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19
Q

AML, ALL

A

incr in common myeloid / lymphoid progenitor

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20
Q

AL pathology

A

decr rbc, platelets, wbc, incr blasts > 20%

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21
Q

AL clin outcome (fib llots)

A

fatigue, infection, bleeding. leukostasis, tissue infiltration, organ fail, enlarged lymph nodes/spleen

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22
Q

AL etiology - idiopathic

A

acquired somatic mutations

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23
Q

AL etiology - incr rate of mutations (gopf)

A

genotoxic exposures, history of other blood cancer, genetic predisposition syndrome, strong fam history

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24
Q

genetic predisposition syndrome

A

fanconi anemia

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25
history of other blood cancer
CML, MDS
26
genotoxic exposures (rbcs)
radiation, benzene, chemo for another cancer, smoking
27
HSC mutations incr w
age
28
2 hit model of leukemogenesis
differentiation block + enhanced prolif = AL
29
differentiation block
loss of fxn of TFs (xsomal translocations like PML-RARa)
30
enhanced prolif
gain of fxn mutations of tyrosine kinases
31
how to assess xsomes
g-banding karyotype (G = geimsa stain... dark bands = gene poor, heterochromatin)
32
AML recurring translocations
t(8;21) & inv(16) related to CBF core binding factor... t(15;17) PML-RARA
33
cbf translocations do what ?
impair cellular differentiation. maturation arrest
34
t(8;21)
RUNX1T1 / ETO (bind CBFa)
35
inv(16)
MYH11 / smooth muscle myosin SMMHC(bind CBFb)
36
ATRA induces what?
t(15;17) blast differentiation
37
ATRA overcomes what?
overcome differentiation block imposed by t(15;17) ... targeted therapy.
38
ATRA
all trans reitnoic acid
39
other successful AML therapies?
not much. chemo indiscriminately targets dividing cells (AML, hair follicles, hut lining)
40
AML cytogenetic risk stratification
good - t(8;21), t(15;17), inv(16). (cbf & pml-rara) intermed - normal.
41
about 50% AML patients have NORMAL karyotypes. no identifiable xsomal abnormalities. what is genetic basis for leukemia then?
NGS reveals somatic mutations (pathogenesis)
42
massively parallel seq tech to measure incorporation of fluorescent dna bases ACTG
1. prep genomic dna sample (fragment, ligate adaptors) 2. attach dna to surface (inside flow cell chans) 3. determine 1st base (add 4 labelled reversible terminators, primers, dna pol) 4. image 1st base (laser excitation, emit flor) 5. determine 2nd base (repeat cycle)
43
NGS tech
millions of wells. nucleotide incorporate into dna, release H+. ion semiconductor seq
44
ion semiconductor seq
pH sensors below sample wells record digital seqs
45
NGS analysis
align short seqs to reference human genome. call variants
46
4 tiers of dna mutations
1. AA coding regions (annotated exons) 2. regulatory. highly condensed. 3. nonrepetitive. unique from 1, 2 4. repetitive, noncomplex. (3 & 4... junk?)
47
tier 1 = coding exons comprise only
1.3% genome. mutations here ~important. (know little about others)
48
traditional 2 hit
TF fusions (xsomal transloc) & activated signalling (TK mutation).
49
AML genomes ~contain how many tier 1 mutations?
~12. (2-3 are driver mutations found in other AML patients)
50
AML ~less complex at what level than other cancers
less complex genetic level
51
traditional 2 hit model
KIT, other TKs, RUNX1-RUNX1T1, MYH11-CBFb
52
IDH1 & 2 isocitrate dehydrogenase
metabolic enzymes also involved in AML
53
advancements for leukemia
mutant IDH inhibitors & darwinian pre-leukemia
54
mutant IDH1/2 turns a-ketoglutarate to what onco-metabolite
2HG (2 hydroxyglutarate) (instead of isocitrate)
55
2HG blocks what
HSC differentiation . (contrib to AML)
56
[mutant IDH] inhibitors can do what
reverse blockade (like ATRA w PML-RARA)
57
darwinian pre leukemia (common)
leukemia after 5 mutations. before that, it's pre-leukemic HSC (acute is not so acute)
58
~10% old adults have detectable 1st hit mutations in what?
peripheral blood (esp DNMT3A, TET2, ASXL1)
59
~10% old adults have detectable 1st hit mutations... what to do?
focus on PB surveillance (predict AML, early targeted therapy)
60
~10% old adults have detectable 1st hit mutations... risks?
11x incr risk getting hematological cancer, 50x risk when mutant clone >20% PB cells
61
how AL arises?
HSC acquire mutations, impair differentiation potential, impart prolif advantage to mutant clones

PATH310 (8 decks)

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