7.李小秋 弥漫性大B细胞淋巴瘤中MYC蛋白失调由BCR-PI3K-AKT信号驱动.pptx

Xiao-QiuLi,M.D.,Ph.D.

FudanUniversity

ShanghaiCancerCenter

April1,2017,Suzhou

asapromisingbiomarkertopredicttherapeuticresponseandsurvival*

lHowever,otherthanasmallsubsetofcasesinwhichMYCisdysregulatedthroughMYCgenestructuralaberrations(rearrangementoramplification),themechanismdrivingMYCoverexpressionislargelyunknown

lItisofgreatimportancetofullyunderstandthe

mechanismsbehindMYCdysregulation,whichcouldleadtoapracticaltherapeutictarget

*CookJR,etal.AmJSurgPathol2014;38,494-501;

YeQ,etal.Oncotarget2016;7(3):2401-16

YeQ,etal.Oncotarget2016;7(3):2401-16

YeQ,etal.Oncotarget2016;7(3):2401-16

ExpressionofMYCproteininDLBCL

WangWG,etal.UnpublisheddatafromFUSCC

t(8)(q24)/myc

MYC

proteasomepathway

lWedemonstratedthatB-cellreceptor(BCR)stimulationiscapableofactivatingthedownstreamPI3K-AKTsignaling,andsubsequentlyphosphorylatingGSK3βatS9site,whichabolishesitsabilitytophosphorylateMYCatT58thus

preventingitsdegradation

lMYCproteindysregulationinDLBCLmaythusbedrivenbytheBCR-PI3K-AKTsignalingviapost-transcriptional

mechanismsandblockingthispathwaywithtargetedagents(e.g.,ibrutinib,idelalisib)mayrevertMYCoverexpression

Fostamatinib

Idelalisib

Ibrutinib

GS1101

situ

lWeinvestigatedtheeffectsofBCR-PI3K-AKT

signalingonMYCproteinlevelandits

lInaddition,weshowedthattheinteractionis

onlypresentinBCR-positiveDLBCLandnotBCR-negativeDLBCL

phosphorylationinvitro

ImmunostainingspectrumofactivatedkeyBCR-PI3K-AKTsignalingmolecules(pSYK

andpAKT)andMYCinDLBCLtissues

andpAKT)involvedinBCR-PI3K-AKT

signalingandMYCproteininDLBCLtissues

inhibitiononthemodificationandlevelof

MYCproteininDLBCLcelllines

MYCproteinlevel

waslowerinde

novoDLBCL,

BCR-thanthatof

DLBCL,BCR+(a);

pMYCandMYC

totalproteinlevelrespondedto

neit