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PATH310 > AL 1 > Flashcards

AL 1 Flashcards

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
Q

history of other blood cancer

26
Q

genotoxic exposures (rbcs)

A

radiation, benzene, chemo for another cancer, smoking

27
Q

HSC mutations incr w

28
Q

2 hit model of leukemogenesis

A

differentiation block + enhanced prolif = AL

29
Q

differentiation block

A

loss of fxn of TFs (xsomal translocations like PML-RARa)

30
Q

enhanced prolif

A

gain of fxn mutations of tyrosine kinases

31
Q

how to assess xsomes

A

g-banding karyotype (G = geimsa stain… dark bands = gene poor, heterochromatin)

32
Q

AML recurring translocations

A

t(8;21) & inv(16) related to CBF core binding factor… t(15;17) PML-RARA

33
Q

cbf translocations do what ?

A

impair cellular differentiation. maturation arrest

34
Q

t(8;21)

A

RUNX1T1 / ETO (bind CBFa)

35
Q

inv(16)

A

MYH11 / smooth muscle myosin SMMHC(bind CBFb)

36
Q

ATRA induces what?

A

t(15;17) blast differentiation

37
Q

ATRA overcomes what?

A

overcome differentiation block imposed by t(15;17) … targeted therapy.

38
Q

ATRA

A

all trans reitnoic acid

39
Q

other successful AML therapies?

A

not much. chemo indiscriminately targets dividing cells (AML, hair follicles, hut lining)

40
Q

AML cytogenetic risk stratification

A

good - t(8;21), t(15;17), inv(16). (cbf & pml-rara) intermed - normal.

41
Q

about 50% AML patients have NORMAL karyotypes. no identifiable xsomal abnormalities. what is genetic basis for leukemia then?

A

NGS reveals somatic mutations (pathogenesis)

42
Q

massively parallel seq tech to measure incorporation of fluorescent dna bases ACTG

A
  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
Q

NGS tech

A

millions of wells. nucleotide incorporate into dna, release H+. ion semiconductor seq

44
Q

ion semiconductor seq

A

pH sensors below sample wells record digital seqs

45
Q

NGS analysis

A

align short seqs to reference human genome. call variants

46
Q

4 tiers of dna mutations

A
  1. AA coding regions (annotated exons)
  2. regulatory. highly condensed.
  3. nonrepetitive. unique from 1, 2
  4. repetitive, noncomplex.
    (3 & 4… junk?)
47
Q

tier 1 = coding exons comprise only

A

1.3% genome. mutations here ~important. (know little about others)

48
Q

traditional 2 hit

A

TF fusions (xsomal transloc) & activated signalling (TK mutation).

49
Q

AML genomes ~contain how many tier 1 mutations?

A

~12. (2-3 are driver mutations found in other AML patients)

50
Q

AML ~less complex at what level than other cancers

A

less complex genetic level

51
Q

traditional 2 hit model

A

KIT, other TKs, RUNX1-RUNX1T1, MYH11-CBFb

52
Q

IDH1 & 2 isocitrate dehydrogenase

A

metabolic enzymes also involved in AML

53
Q

advancements for leukemia

A

mutant IDH inhibitors & darwinian pre-leukemia

54
Q

mutant IDH1/2 turns a-ketoglutarate to what onco-metabolite

A

2HG (2 hydroxyglutarate) (instead of isocitrate)

55
Q

2HG blocks what

A

HSC differentiation . (contrib to AML)

56
Q

[mutant IDH] inhibitors can do what

A

reverse blockade (like ATRA w PML-RARA)

57
Q

darwinian pre leukemia (common)

A

leukemia after 5 mutations. before that, it’s pre-leukemic HSC (acute is not so acute)

58
Q

~10% old adults have detectable 1st hit mutations in what?

A

peripheral blood (esp DNMT3A, TET2, ASXL1)

59
Q

~10% old adults have detectable 1st hit mutations… what to do?

A

focus on PB surveillance (predict AML, early targeted therapy)

60
Q

~10% old adults have detectable 1st hit mutations… risks?

A

11x incr risk getting hematological cancer, 50x risk when mutant clone >20% PB cells

61
Q

how AL arises?

A

HSC acquire mutations, impair differentiation potential, impart prolif advantage to mutant clones

PATH310 (8 decks)

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