Thecancerepigenomeismarkedlyaberrant,andchromatinfactorsarecommonlymutatedinmany malignancies.Recentfunctionalstudiessuggestthatchromatinmis-regulationcanpromotede-differentiation andself-renewalofcancercells.However,theepigeneticmechanismsbywhichcancercellfateprogramsare impairedarepoorlyunderstood.Here,Iaimtoaddressthisquestionintwocancersthatareclearlydrivenby chromatinmis-regulation:acutemyeloidleukemia(AML)andpediatrichighgradegliomas(HGGs)suchas diffuseintrinsicpontineglioma(DIPG).AMLdrivermutationscommonlyinvolvetranslocationsofchromatin regulatorygenes,andDIPGdrivermutationsoccurinhistoneH3in80%ofcases.BothAMLandHGGsarise inpoorly-differentiatedcells,andIhypothesizethatchromatinfactorshelpsustaintheseimproper differentiationprograms.?Differentiationtherapy?aimstotreatsuchcancersbyinducingcellularmaturationto disableself-renewalandhaltproliferation.Whiledifferentiationtherapyhasonlybeenusedinthe promyelocyticsubtypeofAML(APL),mypreliminarydatasuggestthatthisapproachmaybesuccessfulin non-APLAMLsandHGGsifthecriticalepigeneticprogramsregulatingcellfatecanbeidentifiedand manipulated.Indeed,wehavealreadyobtainedleadsonpromisingsmallmoleculeinhibitorsandgenetic targetsthatpromotedifferentiation.Inthisproposal,Iwilltakesimilarstrategiestointerrogatetheepigenetic basisofAMLandHGGcancercellfate.Myapproachwillinvolve(1)Integrativeepigenomicprofilingof induceddifferentiationprogramsingenetically-definedorpatient-derivedcancercelllinemodelswithrelevant driverstoidentifya?roadmap?tocancercelldifferentiation,(2)HighthroughputCRISPR-Cas9-based screeningofthesecellularmodelstoidentifychromatinfactorsthatregulatedifferentiation,(3)Biochemical analysestoidentifythemolecularmechanismsbywhichexistingscreenhitsandthosefoundinfuturescreens manipulatechromatintoinfluencecancercellfate,and(4)Validationoffindingsinpre-clinicalanimalmodels andinclinicalsampleanalyses.WhileIwillleadallaspectsofthisinvestigation,Iwillhavedirectsupportfrom severalworldauthoritiesinAMLandHGG.Ultimately,thegoalofthisprojectistoidentifynoveltherapeutic targetsandapproachesforAMLandHGG.Inthefuture,myaimisforthisworktoopenthedoortothe generalizableconceptofusingepigeneticmanipulationtotherapeuticallytargetcancercellidentityprograms.
Acute myeloid leukemia (AML) and gliomas both display abnormal organization of DNA, which contributes to their rapid growth and inability to differentiate into mature, non-dividing blood or brain cells, respectively. Our goals are to understand how DNA organization influences cellular decisions between growth vs. differentiation into mature cell types. We will use a combination of genetic- and chemical-based assays and animal cancer models, to identify genes that contribute to the changes in DNA organization leading to excessive cell growth in AML and gliomas, and we will explore ways of targeting these genes therapeutically.
| Sheng, Wanqiang; LaFleur, Martin W; Nguyen, Thao H et al. (2018) LSD1 Ablation Stimulates Anti-tumor Immunity and Enables Checkpoint Blockade. Cell 174:549-563.e19 |
