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Leukemiainchildrenwith

Downsyndrome

JohnCrispino

NorthwesternUniversity

July2013

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Leukemia

AbnormalproliferaBonofcertainbloodcellsattheexpenseofothers

MalignantcellsareoFenundifferenBated,immatureprogenitors

Lymphoidleukemiasarecausedbydefectsinimmunecells(suchasandTcells)

Myeloidleukemiasarecausedbychangesinmyeloidcells(suchasmonocytesandmegakaryocytes)

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looddisordersinchildrenwith

Downsyndrome

Infantsfrequentlyshowabnormalbloodcounts UniquelysuscepBbletoTransientMyeloproliferaBveDisorder(atbirth)

300-500foldincreasedriskofAcuteMegakaryoblasBcLeukemia(AMKL),arare

formofmyeloidleukemia(ages1-5)

20-foldincreasedriskof-cellAcuteLymphoblasBcLeukemia(ALL),a

commonchildhoodleukemia(ages5andup)

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AcuteMegakaryoblasBcLeukemia

inDownsyndrome

TMD Presentsatbirth Affectsasmanyas1in10infantswithDS,

butisunder-diagnosed

OFenundergoesspontaneousremission 20-30%ofdiagnosedTMDpaBents

developAMKLbyagethree

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AcuteMegakaryoblasBcLeukemia

inDownsyndrome

TMD Presentsatbirth Affectsasmanyas1in10infantswithDS,

butisunder-diagnosed

OFenundergoesspontaneousremission 20-30%ofdiagnosedTMDpaBents

developAMKLbyagethree

AMKLMedianage2years Affects1in500childrenwithDS Requirestreatment:current

therapiesprovide>80%5yrES

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KeyquesBonsregardingmyeloidleukemiainDS

WhatistherelaBonshipbetweenTMDandAMKL?

WhyareinfantswithDSpredisposedtoleukemia?

WhatgeneBcfactors/mutaBonspromoteTMDandsubsequentAMKL?

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Disease-AssociatedMutaBons

AmutaBonisachangeinthenormalbasepairsequenceofDNA

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Disease-AssociatedMutaBonsAlter

ProteinuncBon

uncBonalprotein NonfuncBonalormissingprotein

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TMDandDS-AMKLpaBentshave

mutaBonsinGATA1

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Impact

Diagnos.c:GATA1mutaBonsaredetectedinnearly5%bloodsampledfrominfantsbornwithDS

Manychildrenhavesub-clinicalcasesofTMD,butareatincreasedriskofAMKL

Carefulmonitoringofbloodinnewbornsandchildrenisneeded

Clinical:carefulmonitoringGATA1mutaBonsinchildrenaFerTMDmayallowforearlydetecBonofAMKL

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Excessive "proliferation"

Spontaneous regression!

Trisomy 21!

Meiosis I/II! Birth! 2-3 years!

How do GATA-1mutations promote

leukemia?

Additional mutations"AMKL"

JAK2/3"FLT3"MPL

What is the role ofTrisomy 21?

GATA1 !mutation! TMD! AMKL!

SMC"DCAF7"RAD21

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MouseModelsofDS

Olsonetal.,2004

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uildingamousemodelofDSAMKL

Ts1RhrmiceHighplateletcountandincreasedmegakaryocytes

butnoleukemia

Ts1Rhr/Gata1mutantmiceMoreseverediseasewithincreased

megakaryocytesandhigherplateletcount

Noleukemia Ts1Rhr/Gata1/MPLmutant

DiseasethatcloselyresemblesDS-AMKL

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Conclusions/currentstudies

WehavefoundthatthecombinaBonof+21,GATA1mutaBonandathirdmutaBonleadsto

DS-AMKLinamousemodel

Thisprovidesaplaormtotestnewtherapies WearetesBngtwonewtherapies

MegakaryocytedifferenBaBonagentsinAMKLDYRK1AinhibitorsforbothinAMKLand-ALL

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Thanksto:

RallyoundaBon

earNecessiBes

SamuelWaxmanCancerResearchoundaBonNaBonal Cancer InsBtute