john crispino: leukemia in children with down syndrome
Post on 02-Apr-2018
223 Views
Preview:
TRANSCRIPT
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
1/16
Leukemiainchildrenwith
Downsyndrome
JohnCrispino
NorthwesternUniversity
July2013
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
2/16
Leukemia
AbnormalproliferaBonofcertainbloodcellsattheexpenseofothers
MalignantcellsareoFenundifferenBated,immatureprogenitors
Lymphoidleukemiasarecausedbydefectsinimmunecells(suchasandTcells)
Myeloidleukemiasarecausedbychangesinmyeloidcells(suchasmonocytesandmegakaryocytes)
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
3/16
looddisordersinchildrenwith
Downsyndrome
Infantsfrequentlyshowabnormalbloodcounts UniquelysuscepBbletoTransientMyeloproliferaBveDisorder(atbirth)
300-500foldincreasedriskofAcuteMegakaryoblasBcLeukemia(AMKL),arare
formofmyeloidleukemia(ages1-5)
20-foldincreasedriskof-cellAcuteLymphoblasBcLeukemia(ALL),a
commonchildhoodleukemia(ages5andup)
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
4/16
AcuteMegakaryoblasBcLeukemia
inDownsyndrome
TMD Presentsatbirth Affectsasmanyas1in10infantswithDS,
butisunder-diagnosed
OFenundergoesspontaneousremission 20-30%ofdiagnosedTMDpaBents
developAMKLbyagethree
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
5/16
AcuteMegakaryoblasBcLeukemia
inDownsyndrome
TMD Presentsatbirth Affectsasmanyas1in10infantswithDS,
butisunder-diagnosed
OFenundergoesspontaneousremission 20-30%ofdiagnosedTMDpaBents
developAMKLbyagethree
AMKLMedianage2years Affects1in500childrenwithDS Requirestreatment:current
therapiesprovide>80%5yrES
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
6/16
KeyquesBonsregardingmyeloidleukemiainDS
WhatistherelaBonshipbetweenTMDandAMKL?
WhyareinfantswithDSpredisposedtoleukemia?
WhatgeneBcfactors/mutaBonspromoteTMDandsubsequentAMKL?
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
7/16
Disease-AssociatedMutaBons
AmutaBonisachangeinthenormalbasepairsequenceofDNA
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
8/16
Disease-AssociatedMutaBonsAlter
ProteinuncBon
uncBonalprotein NonfuncBonalormissingprotein
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
9/16
TMDandDS-AMKLpaBentshave
mutaBonsinGATA1
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
10/16
Impact
Diagnos.c:GATA1mutaBonsaredetectedinnearly5%bloodsampledfrominfantsbornwithDS
Manychildrenhavesub-clinicalcasesofTMD,butareatincreasedriskofAMKL
Carefulmonitoringofbloodinnewbornsandchildrenisneeded
Clinical:carefulmonitoringGATA1mutaBonsinchildrenaFerTMDmayallowforearlydetecBonofAMKL
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
11/16
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
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
12/16
MouseModelsofDS
Olsonetal.,2004
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
13/16
uildingamousemodelofDSAMKL
Ts1RhrmiceHighplateletcountandincreasedmegakaryocytes
butnoleukemia
Ts1Rhr/Gata1mutantmiceMoreseverediseasewithincreased
megakaryocytesandhigherplateletcount
Noleukemia Ts1Rhr/Gata1/MPLmutant
DiseasethatcloselyresemblesDS-AMKL
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
14/16
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
15/16
Conclusions/currentstudies
WehavefoundthatthecombinaBonof+21,GATA1mutaBonandathirdmutaBonleadsto
DS-AMKLinamousemodel
Thisprovidesaplaormtotestnewtherapies WearetesBngtwonewtherapies
MegakaryocytedifferenBaBonagentsinAMKLDYRK1AinhibitorsforbothinAMKLand-ALL
-
7/27/2019 John Crispino: Leukemia in Children with Down Syndrome
16/16
Thanksto:
RallyoundaBon
earNecessiBes
SamuelWaxmanCancerResearchoundaBonNaBonal Cancer InsBtute
top related