EZH2 - siesonline · mutazioni oltre JAK2: EZH2 Paola Guglielmelli Università degli studi di...
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Nuove mutazioni oltre JAK2: EZH2 Paola Guglielmelli Università degli studi di Firenze
Transcript of EZH2 - siesonline · mutazioni oltre JAK2: EZH2 Paola Guglielmelli Università degli studi di...
NuovemutazionioltreJAK2:
EZH2
PaolaGuglielmelli
UniversitàdeglistudidiFirenze
Ernstetal.,NatureGene?cs2010
EZH2muta*ons
ThisregionincludesC7orf33,CUL1,EZH2.
Noaberra?onofCUL1
Nineof12withUPDhadEZH2muta?ons
Missense,donor‐splice‐site,in‐framedele?ons,
frameshiRorstopmuta?on
• AnacquiredUPDat7qin12pa?entswithMPN/MDS(N.=148)
• AnacquiredUPDat7qin2pa?entswithMDS(N.=102)
• Oneptpresentedamicrodele?onat7q36.1
Nikoloskietal.,NatureGene?cs2010
EZH2
EEDSUZ12
RBBP4/7
EZH2
• Mappedto7q36.1• Contains20exons• Encodes746aaresidues• 4conserveddomains
SETDOMAINSANT I SANT II CXC
HistoneH3lysine27(H3K27)trimethyla?on
PRC2(Polycomb‐RepressiveComplex2)
• CXCandSETdomainarerequiredforhistonemethyltrasferaseac?vity
EZH2:func*on
TRANSCRIPTIONALSILENCINGOFGENETARGET
• Transcrip?onfactor• Cellfatesignallingcomponents• MammalianX‐chromosomeinac?va?on
SimonJAetal.Muta?onresearch2008;647:21;XiaoYetal.TheInt.J.BiocandCellBiol2011;43:474
Aberra*onsofEZH2incancer
Overexpression‐inhibi?onofgeneexpression(tumor
suppressorgenes)‐imbalanceofPRC2subunitsactsas
dominant‐nega?vethatdesilencetargetgenes
‐affectscytoskeletal‐basedbehaviors(migra?onandinvasionofcancercells)
SimonJAetal.Muta?onresearch2008;647:21;XiaoYetal.TheInt.J.BiocandCellBiol2011;43:474
Morinetal.NatGenet2010;42:181;Yapetal.Blood2010;Tsangetal.JGHepatol2011;26:19;
EZH2muta*ons:«gain‐»vs«loss‐»offunc*on
• AEZH2Y641heterozygousmuta?onhasbeenfoundin7%and22%of
follicularandgerminalcenterlymphomas,respec?vely
• ItassociateswithincreasedlevelsofH3K27me3duetofavoredtri‐
methyla?onofmutantcomparedtowtenzyme:
a«GAIN‐OF‐FUNCTION»muta?on
thatresultsinincreasedtranscrip?onal
repressionofputa?vetumor‐suppressor
genes
Yapetal.Blood2010;Ernstetal.NatureGene?cs2010;Makishimaetal.,Leukemia2011
EZH2muta*ons:«gain‐»vs«loss‐»offunc*on
• Missensemuta?onsinMPN/MDSaremostlylocatedinevolu?onarily
conserveddomainsrequiredformethyltransferaseac?vity,while
trunca?ngandframeshiRmuta?onsaredispersedthroughoutthe
gene
• Thesemuta?ons
resultina“LOSS‐OF‐
FUNCTION”
• Therefore,findingsofmono‐andbi‐allelicinac?va?ngEZH2muta?ons
inMPN/MDSimplythatEZH2mayactasacodominanttumor
suppressorformyelopoiesis
EZH2muta*onsinmyeloiddisorders
Ernstetal.,NatureGene?cs2010
614ptswithmyeloiddisorders
7%EZH2muta?on
NodifferenceinEZH2mRNAexpression
Noprognos?csignificance
inMPNorMDS
AstudyofEZH2muta*onsinmyelofibrosis
•518pt:370PMF,84PPV‐MF,64PET‐MF
•62%JAK2V617F+,4%MPLW515L/K+
Muta?ons:
23muta?onsin30pts(6%)
23ptshadPMF(6%)
7ptshadPPV/PET‐MF(5%)
Muta?onalstatus:
27werehetero,3(10%)hadhomozygousmuta?on
43%JAK2V617F/EZH2mut
noIDH1/2mutated
50%ASXL1mutated
1aa159250428476611738751aa
SETDOMAINSANT
V679M
V704L
D677HR690H
E726V
Y733X
75244_75245het_insT
N322S
R288QL149Q
I150T
Q553X
W60X
R63X
I96I
T573I
R591H
R566HG135RF145S
P132S
SANT
AstudyofEZH2muta*onsinmyelofibrosis
ClinicalcorrelatesofEZH2muta*onsinPMF
•EZH2muta?onsassociatedpreferen?allywithhigh‐riskthan
low‐riskcategory(IWG‐MRT):19.6%vs5.4%P=0.02
•EZH2mutatedpa?entshadgreaterleukocytosisor>1%blast
cellcountatdiagnosis(P=0.02)
•NoclinicalcorrelatesinPPV/PET‐MF
Prognos*csignificanceofEZH2muta*onsinPMF
SURVIVAL:(univariate)
•IWG‐MRTscore•Age•Leukocytosis•Anemia•Plateletcount•Blastcount•Symptoms•<25%V617Fburden•EZH2muta?on
(mul?variate)•IWG‐MRTscore•<25%V617Fburden•EZH2muta?on
EZH2mut
EZH2WT
P<.0001
Mediansurvival:25.7mo(0‐183)inEZH2mutvs41.6mo(0‐340),P=0.001
EZH2mut
EZH2WT
P=.032
99ptsdied(28.1%)atmedianFU39mo
Conclusions
•EZH2muta?onshavebeendetectedin6%ofPMFandPPV/PET‐MF
•InPMFptsareassociatedpreferen?allywithhigh‐riskIPSSscore,leukocytosis
and>1%blastcellcountatdiagnosisinPMFpts;noclinicalcorrela?onsin
secondary‐MF.
•EZH2muta?onsareassociatedwithreducedOSandLFS
•EZH2muta?onsmustrepresentanovelmolecularmarkerassociatedwith
prognosisinPMF.
ThanksTo:
Sez.EmatologiaUniversitàdiFirenze:
Prof.BosiA.BartalucciNiccolòBiamonteFlaviaBoganiCostanzaFanelliTizianaFjerzaRajmondaMalevol?ElisaMar?nelliSerenaPancrazziAlessandroPaoliChiaraPieriLisaSusiniMariaChiaraTozziLorenzoSpolveriniAmbra
Prof.VannucchiAM
IRCCS,Pavia(Italy):BarosiGiovanniVillaniLaura
NGRLWessex,Salisbury,(UK):CrossNicholasCPScoreJoannahHidalgo‐Cur?sClaireErnstThomasDuncombeAndrew
HospitalClínic,IDIBAPs,Barcelona(Spain):CervantesFranciscoMaffioliMargherita
HaematologyResearchLaboratory,Athens(Greek):ZoiKaterina
MedizinischeUniversitätsklinik,Mannheim(Germany):ReiterAndreas
