Leukemia

in children with Down syndrome

John Crispino Northwestern University July 2013

Leukemia
Abnormal proliferaBon of certain blood cells at the expense of others Malignant cells are oFen undierenBated, 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 suscepBble to Transient MyeloproliferaBve Disorder (at birth) 300-500 fold increased risk of Acute MegakaryoblasBc Leukemia (AMKL), a rare form of myeloid leukemia (ages 1-5) 20-fold increased risk of B-cell Acute LymphoblasBc Leukemia (ALL), a common childhood leukemia (ages 5 and up)

Acute MegakaryoblasBc Leukemia in Down syndrome

TMD
Presents at birth Aects as many as 1 in 10 infants with DS, but is under-diagnosed OFen undergoes spontaneous remission 20- 30% of diagnosed TMD paBents develop AMKL by age three

Acute MegakaryoblasBc Leukemia in Down syndrome

TMD
Presents at birth Aects as many as 1 in 10 infants with DS, but is under-diagnosed OFen undergoes spontaneous remission 20- 30% of diagnosed TMD paBents develop AMKL by age three

AMKL
Median age 2 years Aects 1 in 500 children with DS Requires treatment: current therapies provide >80% 5 yr EFS

Key quesBons regarding myeloid leukemia in DS What is the relaBonship between TMD and AMKL? Why are infants with DS predisposed to leukemia? What geneBc factors/mutaBons promote TMD and subsequent AMKL?

Disease-Associated MutaBons
A mutaBon is a change in the normal base pair sequence of DNA

Disease-Associated MutaBons Alter Protein FuncBon

FuncBonal protein

NonfuncBonal or missing protein

TMD and DS-AMKL paBents have mutaBons in GATA1

Impact

Diagnos.c: GATA1 mutaBons are detected in nearly 5% blood sampled from infants born with DS
Many children have sub-clinical cases of TMD, but are at increased risk of AMKL Careful monitoring of blood in newborns and children is needed

Clinical: careful monitoring GATA1 mutaBons in children aFer TMD may allow for early detecBon of AMKL

Trisomy 21!

GATA1 ! mutation!

TMD!

AMKL!

Meiosis I/II!

Birth!

2-3 years!

Additional mutations"
JAK2/3" SMC" FLT3" DCAF7" MPL RAD21 How do GATA-1 mutations promote leukemia?
Excessive " proliferation"

AMKL"

What is the role of Trisomy 21?

Spontaneous regression!

Mouse Models of DS

Olson et al., 2004

Building a mouse model of DS AMKL

Ts1Rhr mice
High platelet count and increased megakaryocytes but no leukemia

Ts1Rhr/Gata1 mutant mice

More severe disease with increased megakaryocytes and higher platelet count No leukemia

Ts1Rhr/Gata1/MPL mutant
Disease that closely resembles DS-AMKL

DYRK1A ERG

Conclusions/current studies
We have found that the combinaBon of +21, GATA1 mutaBon and a third mutaBon leads to DS-AMKL in a mouse model
This provides a plahorm to test new therapies

We are tesBng two new therapies

Megakaryocyte dierenBaBon agents in AMKL DYRK1A inhibitors for both in AMKL and B-ALL

Thanks to: Rally FoundaBon Bear NecessiBes Samuel Waxman Cancer Research FoundaBon NaBonal Cancer InsBtute