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

Think Antibodies. Think Bio-Rad.Explore more resources at bio-rad-antibodies.com/cell