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Diagnostic Molecular Pathology > 33 Acute Myeloid Leukemia AML > Flashcards

33 Acute Myeloid Leukemia AML Flashcards

1
Q

AML

A

– Acute Myeloid Leukemia

– the most common type of leukemia in adults

– Heterogeneous disease

– The result of somatic genetic alterations in hematopoietic progenitors

– Mutations affect normal proliferation, self-renewal and differentiation

– Inherited AML is rare

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2
Q

What is FAB AML classification system?

A

– French-American-British system for classify AML

– based on cell morphology and immunochemical characteristics

– not showing a significant prognostic difference

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3
Q

Inherited germline mutations link to AML

A

CEBPA
SRP72
DDX41
RUNX1
GATA2

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4
Q

Gilliland and Griffin: two-hit model for AML pathogenesis

A

Class 1 mutations:
– activate signal pathways to promote proliferation and survival of progenitors
– happened later in leukemogenesis

Class 2 mutations:
– affect transcription factors that impair differentiation
– occur early in leukemogenesis
– founder mutations
– stable during the disease course
– class 2 mutations do not coexist

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5
Q

Gilliland and Griffin Class 1 mutations

A

FLT3, KIT, NRAS, KRAS

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6
Q

Gilliland and Griffin Class 2 mutations

A

Gene fusions:
t(8;21) - RUNX1/RUNX1T1
inv(16) - CBFB/MYH11

Gene mutations:
NPM1, CEBPA, RUNX1

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7
Q

AML: t(8;21) (q22;q22) affected gene

A

RUNX1-RUNX1T1

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8
Q

AML: t(15;17) (q22;q12) affected gene

A

PML-RARA

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9
Q

AML: inv(16) (p13.1 q22) or t(16;16) (p13.1;q22) affected gene

A

CBFB-MYH11

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10
Q

AML: t(9;11) (p22;q23) affected gene

A

MLLT3-KMT2A (MLL)

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11
Q

AML: t(6;9) (p23;q34) affected gene

A

DEK-NUP214

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12
Q

AML: inv(3) (q21q26.2) or t(3;3) (q21;q26.2) affected gene

A

GATA2, MECOM (EVI1)

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13
Q

AML: t(1;22) (p13;q13) affected gene

A

RBM15-MKL1

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14
Q

AML with NPM1 mutation affected gene

A

NPM1

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15
Q

AML with biallelic CEBPA mutations

A

CEBPA

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16
Q

Which cytogenetic abnormalities can be used solely to diagnose if the patient has AML or not without considering >20% blast-count rule?

A

t(8;21) : RUNX1-RUNX1T1
inv(16) or t(16;16) : CBFB-MYH11
t(15;17) : PML-RARA

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17
Q

The first step to diagnose AML

A

– morphologic evaluation such as presence of Auer rods
– >20% myeloid blasts and monocytic progenitors

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18
Q

Which immunophenotypic analysis is often used to distinguish AML from lymphoblastic leukemia?

A

Flow cytometry

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19
Q

After established AML in patient, what are the next tests for further subclassification?

A

– Karyotyping
– FISH
– Sanger sequencing

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20
Q

what specimens can be used for AML diagnosis?

A

– blood
– bone marrow aspirate

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21
Q

What cytogenetic abnormalities are classified by WHO as “Favorable” risk category?

A

t(15;17) : PML-RARA

t(8;21) : RUNX1-RUNX1T1

inv(16)/t(16;16) : CBFB-MYH11

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22
Q

What cytogenetic abnormalities are classified by WHO as “Intermediate” risk category?

A

t(9;11) : MLLT3-KMT2A (MLL)

Normal cytogenetics

+8 alone

Other karyotype

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23
Q

What cytogenetic abnormalities are classified by WHO as “Poor” risk category?

A

Complex cytogenetics (>=3 abnormalities)

inv(3)/t(3;3) : GATA2, MECOM (EV11)

t(6;9) : DEK-NUP214

11q23 abnormalities other than t(9;11)

t(9;22)

-5, del(5q)

-7, del(7q)

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24
Q

What gene mutations are classified by WHO as “Favorable” risk category?

A

Normal cytogenetics without FLT3-ITD and with either NPM1 or biallelic CEBPA mutations

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25
Q

What gene mutations are classified by WHO as “Intermediate” risk category?

A

t(8;21) or inv(16)/t(16;16) with KIT mutation

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26
Q

What gene mutations are classified by WHO as “Poor” risk category?

A

Normal cytogenetics with FLT3-IDT mutation

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27
Q

CBF AML

A

Core-Binding Factor AML

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28
Q

What does “Favorable” risk category mean?

A

excellent prognosis
better response to chemotherapy

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29
Q

Function of CBF

A

– transcription factor complex
– role in hematopoiesis

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30
Q

Two subunits of CBF

A

– RUNX1(AML1, CBFA2)
– CBFB

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31
Q

Hematopoietic neoplasms caused by CBF disruption or abnormalities

A

– Myelodysplastic syndrome (MDS)
– Acute lymphoblastic leukemia (ALL)
– AML

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32
Q

Cytogenetic abnormalities or chromosomal abnormalities associated with CBF AML

A
  1. t(8;21) that creates a RUNX1-RUNXIT1 (AML1-ETO) gene fusion
  2. inv(16) or t(16;16) that results in the CBFB-MYH11 gene fusion
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33
Q

If the cytogenetic analysis did not detect t(8;21) or inv(16/t(16;16), CBF AML is suspected by morphology. How do you confirm the diagnosis of CBF AML?

A

Use FISH or RT-PCR to detect t(8;21) or inv(16)/t(16;16)

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34
Q

what gene mutations are frequently seen in CBF AML?

A

Mutations in KIT, FLT3, or RAS

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35
Q

APL

A

Acute Promyelocytic Leukemia

accounts 12% of AML

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36
Q

Cytogenetic abnormality and fusion gene associated with APL

A

t(15;17) – PML-RARA fusion gene

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37
Q

what does t(15;17) – PML-RARA fusion gene do to the APL progression?

A

– halts myeloid progenitor differentiation
– expansion of neoplastic promyelocytes

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38
Q

Gene: RARA

A

retinoic acid receptor alpha

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39
Q

Gene: PML

A

promyelocytic leukemia

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40
Q

t(15;17), what are the breakpoints on chr. 17?

A

chr. 17 intron 2 of RARA gene

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41
Q

t(15;17), what are the breakpoints on chr. 15?

A

chr. 15 intron 6 (bcr1: 55% of APL cases)

chr. 15 exon 6 (bcr2: 5% of APL cases)

chr. 15 intron 3 (bcr3: 40% of APL cases)

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42
Q

3 PML-RARA isoforms

A

1) Long: L or bcr1: 55% of APL cases

2) Variant: V or bcr2: 5% of APL cases

3) Short: S or bcr3: 40% of APL cases)

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43
Q

% APL cases of PML-RARA with bcr1 isoform?

A

55%

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44
Q

% APL cases of PML-RARA with bcr2 isoform?

A

5%

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45
Q

% APL cases of PML-RARA with bcr3 isoform?

A

40%

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46
Q

Which PML-RARA isoform has the least % of APL?

A

bcr2 isoform

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47
Q

A minor subset of APL cases harbor variant translocations that fuse RARA with a different partner genes other than PML. What are these partner genes for a variant RARA translocation?

A

BCOR, FIP1L1
NPM1, NUMA
PRKAR1A
STAT5B
ZBTB16 (PLZF)

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48
Q

What are the RARA alternative partner genes to cause APL?

A

BCOR, FIP1L1
NPM1, NUMA
PRKAR1A
STAT5B
ZBTB16 (PLZF)

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49
Q

what is the APL-specific treatment that must be given ASAP after the initial diagnosis?

A

ATRA = all-trans retinoic acid

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50
Q

What causes APL patient death during the first few days after diagnosis?

A

Coagulopathy (凝血病)

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51
Q

ATRA

A

all-trans retinoic acid

52
Q

Which alternative RARA fusion genes lead to poor outcome and resistance to ATRA in APL patients?

A

PLZF-RARA

STAT5B-RARA

53
Q

Residual disease monitoring for APL use which method?

A

RT-PCR of PML-RARA

consecutive negative tests are associated with remission, long-term survival and possible cure

Relapse: two consecutive RT-PCR positive results (one in bone marrow)

54
Q

Which cytogenetic abnormality is very rare and predominantly occur in patient less than 3 years old AML patients?

A

t(1;22)
RBM15-MKL1

55
Q

What is CN-AML?

A

50% of AML lacks chromosomal abnormalities

these are called cytogenetically normal (CN) AML.

56
Q

Genes mutated in CN-AML

A

NPM1
FLT3-ITD
CEBPA

57
Q

Genes mutated in CBF-AML

A

KIT

58
Q

Gene mutations that are tested in guiding post-remission therapy in AML

A

NPM1
FLT3-ITD
CEBPA
KIT

59
Q

% of NPM1 mutations in AML patients

A

30% in all AML patients

50% in CN-AML patients

60
Q

What NPM1 stands for?

A

Nucleophosmin

also called nucleolar protein B23, numatrin, or NO38,

an abundant phosphoprotein

located on chr. 5q35, 12 exons

61
Q

Function of NPM1

A

transport preribosomal particles through nuclear membrane

shuttle between the nucleus and the cytoplasm

62
Q

where is mutated NPM1 localized in a cell?

A

cytoplasm

63
Q

where is wild type NPM1 usually localized in a cell?

A

nucleus

64
Q

NPM1 mutations

A

frameshift mutations within exon 12

a net 4bp insertions

loss of a nucleolar localization signal

generation of a novel nuclear export signal

65
Q

Disease outcome of NPM1 without FLT3-IDT mutation in AML patients

A

better overall survival

event-free survival

better response to treatment

patients are not candidates for allogeneic stem cell transplantations

66
Q

Why do we test NPM1 and FLT3-IDT for CN-AML patients?

A

NPM1 without FLT3-IDT mutation is prognostic favorable

67
Q

Method to detect NPM1 mutations

A

PCR fragment-sizing assay:
PCR amplify exon 12–>capillary electrophoresis

4bp insertions

LOD: 2% in 20% blasts

50 variants known

68
Q

Disadvantages of qPCR detection of NMP1 mutations

A

only designed to detect specific NMP1 mutations

qPCR is better for minimal residual disease (MRD) monitoring

69
Q

FLT3

A

FMS-like tyrosine kinase 3

receptor tyrosine kinase

regulate proliferation of hematopoietic progenitor cells

70
Q

which is the second common gene mutations in AML?

A

FLT3 mutations

25-30% of all AML patients

71
Q

Two types of FLT3 mutations in AML

A
  1. internal tandem duplication (FLT3-ITD)
  2. tyrosine domain mutations (FLT3-TKD)
72
Q

% of AML with FLT3-ITD mutations

A

20-25% of AML

73
Q

% of AML with FLT3-TKD mutations

A

5-10%

74
Q

Function of FLT3-ITD mutations and FLT3-TKD mutations

A

constitutive activation of the FLT3 receptor

75
Q

FLT3-ITD mutations

A

Duplication and tandem insertion of 3 to several hundreds bp of FLT3 gene

insertion located in exon 14 (common) or 15 of FLT3 gene

in-frame mutations

gain-of-function

76
Q

FLT3-ITD mutations detection method

A

PCR fragment-sizing assay:
PCR–> capillary electrophoresis

15% of FLT3-ITD AML patients have multiple IDT mutations

Biallelic ITD shown taller peaks on capillary electrogram than the WT control

77
Q

FLT3-TKD mutations

A

missense mutations such as D835 (codon 835 aspartic acid)

78
Q

The outcomes of AML with the following combinations:
FLT3-ITD + NPM1 mutations
FLT3-ITD + CEBPA mutations

A

poor

79
Q

Is NGS a efficient method for FLT3-ITD testing?

A

No, due to large duplications

80
Q

FLT3-TKD mutations detection method

A

PCR amplification
EcoRV digestion at D835
capillary electropherogram

WT-digested by EcoRV
FLT3-TKD D835 mutants, can not be digested

see figure

81
Q

Are FLT3-ITD mutations good test markers for monitoring MRD?

A

No. FLT3-ITD mutations might be lost during the relapse.

82
Q

CEBPA

A

CCAAT/enhancer-binding protein alpha

a member of the basic region leucine zipper (bZIP) family of TFs

83
Q

CEBPA role in hematopoiesis

A

differentiation of myeloid progenitors

84
Q

% of CEBPA mutations in AML patients

A

8-15% of all AML

commonly seen in CN-AML

85
Q

CEBPA mutations in AML

A

Majority of cases with two mutations:
N-terminal frameshift mutation in one allele
C-terminal in-frame mutation in another allele

Only double mutated CEBPA associated with favorable AML outcomes.

86
Q

CEBPA mutations function in AML

A

loss of function of the differentiation promoting p42 isoform

expression of pro-proliferative p30 isoform

87
Q

How do the CEBPA mutations compared to FLT3 and NPM1 mutations?

A

CEBPA mutations are highly variable and spanned the entire coding region

88
Q

CEBPA mutations detection method

A

fragment-sizing analysis: for insertions and deletions
Sequencing

89
Q

Why NGS is not a preferred method for CEBPA mutations detection method?

A

High GC content of CEBPA

90
Q

Sanger sequencing limitations for CEBPA mutations?

A

low sensitivity (~ 10%)

91
Q

KIT

A

The KIT gene: chr. 4q11-12
a 145-kDa transmembrane glycoprotein

a member of the type III tyrosine kinase family

Binding of stem cell factor (KIT ligand) to the KIT receptor activates downstream signaling pathways important for cell proliferation, differentiation, and survival

92
Q

KIT mutations

A

occur in ~30% of CBF-AML patients

mostly occur in exon 8 or 17

93
Q

KIT Exon 8 mutations in AML

A

small in-frame insertions/deletions that affect codon 419

94
Q

KIT Exon 17 mutations in AML

A

substitution at codon D816 or N822

substitution at codon D816 in CBF-AML (t8;21) associated with a higher risk of relapse

95
Q

RUNX1

A

Runt-related TF 1

role in hematopoietic differentiation

96
Q

RUNX1 mutations

A

10-15% of CN-AML

seen in MDS and AML with myelodysplasia-related changes

initiating events for AML

often found in the absence of fusion genes and NPM1 and CEBPA mutations

97
Q

MDS

A

Myelodysplastic syndrome

a type of blood cancer (leukemia) in which the bone marrow produces immature blood cells

98
Q

RUNX1 gene mutations in AML

A

substitution, insertions, deletions

throughout the coding region

99
Q

IDH1 and IDH2

A

isocitrate dehydrogenase

are key enzymes that function at a crossroads of cellular metabolism, epigenetic regulation, redox states, and DNA repair

IDH1 and IDH2 are NADP+ dependent, share considerable sequence similarity

100
Q

Where IDH1 expressed?

A

in the mammalian liver and moderately expressed in other tissues

It contains a C-terminal tripeptide peroxisome targeting signal 1 sequence

localizes to the cytoplasm and peroxisome of yeast and mammalian cells

101
Q

Where IDH2 expressed?

A

IDH2 contains an N-terminal mitochondrial signal peptide

localizes to the mitochondria

It is highly expressed in mammalian heart, muscle, and activated lymphocytes

102
Q

% IDH1 and IDH2 mutations in AML

A

15-30% of AML

common in CN-AML

103
Q

IDH 1 and IDH2 mutations

A

substitutions

R132 of IDH1

R140 or R172 of IDH2

IDH1 and IDH2 mutations occur in a mutually exclusive fashion

104
Q

Function of IDH 1 and IDH2 mutations

A

affect active site of IDHs

lead to high level of d-2-hydroxyglutarate (2HG)

105
Q

IDH 1 and IDH2 mutations found in which cancers?

A

AML

glioma

106
Q

DNMT3A

A

DNA (cytosine-5)-methyltransferase 3 alpha

function in DNA methylation

107
Q

% of DNMT3A mutations in AML

A

20% of AML

common in CN-AML

108
Q

DNMT3A mutations

A

affect epigenetic modification of DNA

R882 is the most common DNMT3A mutations (60%)

in-frame and frame-shift mutations

109
Q

DNMT3A mutations testing methods

A

NGS
high resolution melting of R882 (exon23)
Sanger seq of R882 (exon23)

110
Q

KMT2A (MLL)

A

encodes a DNA-binding protein that methylates histone H3

positively regulates expression of target genes, including multiple HOX gene

epigenetic modifier

111
Q

KMT2A (MLL) mutations

A

epigenetic modifier

5-10% of CN-AML

prognosis: inconclusive

112
Q

ASXL1

A

the additional sex combs like-1 gene

a member of trithorax and polycomb (ETP) family

113
Q

ASXL1 function

A

transcriptional regulator

has chromatin-binding activity

chromatin modifier

114
Q

WT1

A

Wilms tumor 1 gene

TF

a tumor suppressor or an oncogene

115
Q

WT1 gene mutations

A

10-15% of CN-AML

germline with WAGR syndrome

majority mutations found are frameshift insertions and deletions on exon 7

116
Q

WAGR syndrome

A

a disorder that affects many body systems and is named for its main features: Wilms tumor, aniridia (無虹膜), genitourinary anomalies, and intellectual disability (formerly referred to as mental retardation)

117
Q

ASXL1 mutations

A

5-10% of CN-AML

prognosis unfavorable

frameshift or nonsense mutations in exon 12

found in AML and MDS

118
Q

TET2

A

ten-eleven-translocation 2 gene

demethylation of DNA

epigenetic modifier

119
Q

TET2 mutations

A

found in AML and MDS

10% of CN-AML

inactivated TET2

increased stem cells renewal and myeloproliferation

120
Q

TP53

A

cell cycle regulator

tumor suppressor

121
Q

TP53 mutations

A

2-5% in CN-AML

75% of TP53 mutated AMLcases have poor outcome

122
Q

RAS

A

membrane associated signaling

regulate proliferation, differentiation and apoptosis

123
Q

KRAS and NRAS mutations

A

~20% in all human cancers

10% of CN-AML

124
Q

Overexpression of genes in AML

A

BAALC - a negative prognostic indicator for CN-AML
ERG
EVI1

associated with worst outcome

125
Q

minimal residual disease testing (MRD) for APL, RT-PCR

A

PML-RARA

126
Q

MRD for CBF-AML, RT-PCR

A

RUNX1-RUNX1T1

CBFB-MYH11

127
Q

Future testing methods for AML

A

NGS

microRNA

Diagnostic Molecular Pathology (12 decks)

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