Why do children with DS get

leukemia and what can we do

about it?
John Crispino, PhD
Division of Hematology/Oncology

Leukemia
Abnormal proliferation of certain blood
cells at the expense of others
Malignant cells are often
undifferentiated, immature
progenitors
Lymphoid leukemias are caused by
defects in immune cells (such as B
and T cells)
Myeloid leukemias are caused by
changes in myeloid cells (such as
monocytes and megakaryocytes)

Blood disorders in children with

Down syndrome
Infants frequently show abnormal blood counts
Uniquely susceptible to
Transient Myeloproliferative Disorder (at birth)
>150-fold increased risk of
Acute Megakaryoblastic Leukemia (AMKL), a
rare form of myeloid leukemia (ages 1-5)
20-fold increased risk of
B-cell Acute Lymphoblastic Leukemia (ALL),
a common childhood leukemia (ages 5 and up)

Transient Myeloproliferative Disorder

A pre-leukemia unique to
infants with DS
Has its origins in utero
May occur in as many as 30% of
infants
But the clinical presentation is
highly variable

Diagnosed by elevated white

blood cell count
Generally untreated
10-20% of TMD patients develop
AMKL by age three

Acute Megakaryoblastic Leukemia

in Down syndrome
AMKL
An otherwise rare form of
acute myeloid leukemia
Median age 2 years
Affects 1 in 500 children
with DS
Requires treatment
Caused by a combination
of at least three genetic
alterations

Key questions regarding myeloid

leukemia in children with Down
syndrome
What is the relationship between
TMD and AMKL?
What genetic factors/mutations
promote TMD and subsequent
AMKL?
Why are infants with DS
predisposed to leukemia?

Disease-Associated Mutations
A mutation is a change in the normal base pair sequence of DNA

Disease-Associated Mutations
Alter Protein Function

Functional protein

Nonfunctional
or missing
protein

TMD and DS-AMKL patients have

mutations in GATA1

An extra T is inserted into the DNA

Oxford Imperial DS Cohort Study

Studied 200 newborns with DS
Found that the incidence of GATA1
mutations was 29% of the population
Defined TMD as >10% leukemia cells and
a GATA1 mutation
11% TMD cases with a GATA1 mutation
progressed to AMKL
None of those cases without a GATA1
mutation progressed

Roberts et al, Blood 2013

Trisomy 21

Meiosis I/II

GATA1
mutation

TMD

AMKL

Birth

2-3 years

Additional mutations
JAK2
JAK3
FLT3
MPL

RAD21
STAG2
CTCF
EZH2

Excessive
proliferation

Spontaneous regression
Sandeep Gurbuxani MD/PhD

AMKL

How does trisomy 21

promote leukemia?

How can we better

treat the disease?

Outcomes for AMKL

Children with DS have better than an
80%
5-year overall survival (OS)
The GATA1 mutation imparts an
increased sensitivity of the leukemia
cells to chemotherapy

Outcomes for children without DS are

lower than in those with DS
5 yr OS approximately 40% overall,
although some genetic subtypes fare
better, some worse

Impact of our research

Diagnostic: GATA1 mutations can be
detected in nearly 30% of blood from
infants with DS
Many children have sub-clinical cases of
TMD, but are at increased risk of AMKL

Clinical: careful monitoring GATA1

mutations in children after TMD may
allow for early detection of AMKL

Acute Lymphoblastic Leukemia (ALL)

B-ALL is the most common form of childhood
cancer
5 year overall survival for B-cell ALL
is approximately 90%
o Relapsed patients have
overall survival about 30%
o Relapse rate without DS: 15%
o Relapse rate with DS: 26%
In addition to higher relapse rate,
children with DS are hypersensitive to
chemotherapy and have higher rate of
treatment related mortality

Outcomes for B-ALL

Study

population

Survival

International ALL
Ponte di Legno
Working Group
1995-2004
Buitenkamp et al,
Blood 2014

4445 children without

DS
653 children with DS

8 yr EFS
64%
8 yr OS
74%

Childrens Oncology
Group
1999-2005
Maloney et al, Blood
2010

81% vs
89% vs

2 yr TRM
7%

2% vs

2731 children without

DS
80 children with DS

5 yr EFS
70%
5 yr OS
86%

78% vs

UK ALL study
3040 children without
2003-2011
DS
Patrick et al, BJH 2014 86 children with DS

5 yr EFS
66%
5 yr OS
70%

90% vs

88% vs
92% vs

Challenges to treatment of DS-ALL

Increased toxicity to chemotherapy
and higher treatment related
mortality
There may be decreased protocol
adherence in children with DS
Data suggest that decreased doses of
methotrexate and mercaptopurine may
contribute to inferior outcome

Genetics of B-ALL in children with

Down syndrome
The genetics of B-ALL is more
complicated than that of AMKL
DS-AMKL can be modeled in mice with
three mutations, but it takes five to
generate a DS-ALL model

There are many mutations that in

common with B-ALL, but some are
much more common prevalent in DSALL

Mouse Models of DS

Olson et al., Science 2004

mice
Ts1Cje

DSCR

DSCR

Ts16

Tc1

Ts65Dn Ts1Cje

Ts1Rhr

AML1
CBR1
CBR3
C21orf5
AK009785
KIAA0136
CHAF1B
CLDN14
SIM2
HLCS
DSCR6
DSCR5
TTC3
DSCR3
DYRK1A
As-DYRK1
KCNJ6
KCNJ15
As-KCNJ15
ERG
ETS2
DSCR2
WDR9
HMG14
WRB
C21orf13
SH3BGR
B3GALT5
IGSF5
PCP4
DSCAM
As-DSCAM
BACE2
MX1
C21orf1

ERG
DYRK1A
CHAF1B
HMGN1

DYRK1A inhibitors reduce the

growth of
acute lymphoblastic leukemia cell
lines

Conclusions
Trisomy 21 predisposes children to
leukemia
Children with DS have a better prognosis
for AMKL, but a worse prognosis for B-ALL
Less toxic and more effective therapies are
needed for both forms of cancer
Research aimed at understanding the
nature of the predisposition and the genetic
basis of the disease will identify new
strategies to treat these tumors

Current studies
Mouse models of DS-AMKL and DSALL have been created
They have improved our understanding
of the genetic basis of the disease
They provide a platform to test new
therapies

We are testing two new therapies

Megakaryocyte differentiation agents
in AMKL
DYRK1A inhibitors for DS-ALL

JohnCrispino,PhD
jcrispino@northwestern.edu

Shannon L. Maude et al. Blood 2015;125:4017-4023

2015 by American Society of Hematology