SnapShot: Acute Myeloid LeukemiaBernd B. Zeisig, Austin G. Kulasekararaj, Ghulam J. Mufti, and Chi Wai Eric SoDepartment of Haematological Medicine, King’s College London, London SE5 9NU, UK
20%-25% (28%-35%); High blast count; Poor prognosisespecially in cases with high mutant to WT allelic ratio
5%-7% (10%-14%); Prognostic impact remains controversial
10% (9%-14%); Enriched in CBF AML; Prognosis unknown
<5% (<5%); 25-30% in CBF leukaemia
<2% (2%); Prognosis unknown
25%-30% (40%-65%); M4 blast morphology lacks CD34 expression; Hox gene upregulation; Favorable prognosis inthe presence of FLT3WT; Female preponderance
5%-10% (10-19%); Favorable prognosis if biallelic mutation
5%-13% (6-25%); Enriched in trisomy 13 and FAB M0; Poor prognosis
10% (10%-13%); Associated with M0 FAB type; Poor prognosis
2%-4% (<2%); Predominantly in CK-AML; Very poor prognosis
20%-25% (32%-35%); Heterozygous R882 mutations accountfor 40%-60% of mutations; Poor prognosis in NK-AML
12%-22% (25%-30%); Mutant IDH1 & 2 are mutually exclusive; IDH1 mutations enriched in patients with NPM1mut;IDH1 is localized in cytoplasm and peroxisomes
7%-15% (15%-23%); Mutually exclusive to IDH1/2 mutations; More prevalent in secondary AML especially MPN
3% (3%-5%); Poor prognosis
<2% (<1%); Enriched in MDS/MPN; Prognosis unknown
<2% (2%-5%); Enriched in trisomy 11
Deregulated in inv(3)(q21q26); Poor prognosis
Poor response to chemotherapy; Correlated with NPMWT and high BAALC expression
Lineage-, Sca-1+, c-KIT+ population
Common myeloid progenitor
Granulocyte macrophage progenitor
Positive impact
Negative impact
Not signi�cant
Colors represent different clones
Indicates (epi)genetic mutations
Leukemic stem cell
Other Leukemic (non-stem) cells
Leukemic subclone originating from LSC
Leukemic subclone originating from non-LSC
Self-renewal
High expression in NK and +8; Poor prognosis
Poor prognosis in CK and NK AML
Increased in FAB M1/M2, CEBPAmut; Favorable prognosis
Gene
Favorable risk (5 yr OS: 45%-80%)
40%-45% of AML cases
Aberration
t(15:17)
t(8:21)
inv(16)
NK with NPMmut
& no FLT3-ITD
NK with biallelicCEBPAmut
7-12
5-8
5-8
18-25
6-12
NK with FLT3-ITD
NK with NPMWT & no FLT3-ITD
t(9:11)
Other cytogenetic abnormalities not included elsewhere
15-20
10-17
2-3
5-8
11q23,inv(3)/t(3;3)/EVI-1t(6;9)/DEK-NUP214 -7/7q--5/5q-17p deletionsCK
3-5~1~13-52-3~210-12
Standard induction cytotoxic therapy(“3+7”), followed by postremission therapy with high dose cytarabine
ATRA as a differentiating agent with anthracycline based chemotherapy in t(15;17)
Standard induction cytotoxic therapy (“3+7”), followed by postremission consolidation
Allogeneic HSCT should be considered as main modality of consolidation, especially in patients with FLT3-ITD
t(15:17), PML-RARα
11q23, MLL fusion
t(8:21), AML1-ETO; inv(16), CBF-MYH11
t(8:21), AML1-ETO
Standard induction cytotoxic therapy (“3+7”), although dismal outcome with chemotherapy alone
Allogeneic HSCT should be offered in clinical remission 1
Consider use of investigational and novel agents
Frequency (%) Frequency (%) Frequency (%)
25%-35% of AML cases 25%-30% of AML cases
Pro
gn
ost
ic c
ateg
ory
Cur
rent
the
rap
ies
Intermediate risk (5 yr OS: 20%-40%) Adverse risk (5 yr OS: 5%-20%)
FLT3-ITD
FLT3-TKD
NRAS
C-KIT
PTEN
NPM1
CEBPA
RUNX1
WT1
TP53
DNMT3A
IDH1/IDH2
TET2
ASXL1
EZH2
MLL-PTD
EVI-1
MN1
BAALC
Loss offunction
Impact on
PTENHSC- +
+-
---
-NS
NS
LSC
β-catenin
BMIHOX
ERG
miR-181
Sig
nal
ling
Tran
scri
pti
on
fact
ors
(TF)
Ep
igen
etic
mo
difi
ers
Ove
rexp
ress
ed
Frequency (in NK-AML) and comments
Self-renewal pathways
Aberration Aberration
DNMT3a*
MLL
Clinical Features and Risk Stratification of AML
Molecular Mechanisms, Recurrent Gene Mutations, and Emerging Targeted Therapies in AML
Cell of Origin and Clonal Evolution Model of Leukemic Stem Cells
Cytogenetic Aberrations in AML
Normalkaryotype
(NK)
t(15:17)
t(8:21)inv(16)11q23
Complexkaryotype
(CK)
Others
Adult AML Childhood AML
Trisomy 8-7+21
45%
10%
5%5%
5%
20%
10%
20%
10%
10%
5%
10%
7%
21%
5%4%8%
DNMT HDACi
PI3Ki
mTORi
FLT3i Dasatinib GO
EPZ004777
PRMT1i
DNMTi
HATiPRMT1i
iBET/JQ1
iMenin
As203 ATRA RXRagonist
EZH2 HDAC
RXRRARαPML
SHCsPI3K
PDK1 SGK
PKCAKT
mTOR FOXO Cell survivalProliferation
Inhibition of apoptosisTranslation
*mutated in AML
RAS*
MEK
ERK
PTEN*
FLT3* c-KIT* CD33
Menin
PRMT1
DOT1L
fusion
P-TEFb
BRD4
CBF
Me
Me
Ac
Ac
Ac
Ac
Ac
Ac
Me
Me
Me
MeMe Me Me
Me
HDACNcoR
fusionTF*
TET2*
α-KGα-KG α-HGα-HG
mutatedIDH2*
mutatedIDH1* IDH2IDH1
isocitrateisocitrate
TF*EZH2*
AML1
CBPPRMT1
ETO
H4R3
H3K27
H4R3 H3K79
H3K27H3K27H3K27
H3K27
PAFc
NUCLEUS
NORMALHEMATOPOIESIS PRE-LEUKEMIA OVERT
LEUKEMIACLINICAL
REMISSION RELAPSE
MITOCHONDRION
ASXL1*
HDACi
HSC
MPP
CLP
ProT ProB MEP GMP
CMP
Pre-LSC
LSK
CMP
GMP
LSC
LSC-SC
SC
NS
Initiatingevent
Cooperatingevent
Other cooperatingevent
e.g., MLL fusion/PML-RARα
e.g., FLT3
FoundingAML clone
LSK
LMPP
LSC1-SC1LSC1-SC1
LSC1LSC1SC1SC1
SC2SC2
LSC2LSC2
LSC1-SC1LSC1-SC1
LSC1LSC1
LSC2LSC2
LSC1-SC1LSC1-SC1
LSC1LSC1
LSC2LSC2
CHEMOTHERAPY
CpGCpG
CpGCpG
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