Abstract
Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL).We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell-specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia.
| Original language | English (US) |
|---|---|
| Article number | abq8437 |
| Journal | Science Advances |
| Volume | 8 |
| Issue number | 49 |
| DOIs | |
| State | Published - 2022 |
Funding
Acknowledgments: W e thank D. Fang\u2019s laboratory (Northwestern University) for pro viding the Usp7knockoutmice.Funding:TheNtziachristoslaboratoryisorhasbeensupportedbythe ResearchFoundationFlanders(FWO,G0F4721N)andstart-upfundsfromtheDepartmentof BiomolecularMedicine,GhentUniversity,theNCI(R00CA188293andR01CA248770),the NationalScienceFoundation,theHartwellFoundation,aGileadResearchScholarship,the American Society of Hematology, the Leukemia Research Foundation, the St. Baldrick\u2019s Foundation, the H Foundation, the Gabrielle\u2019s Angel Foundation, the Elsa Pardee Foundation, andtheZellFoundation.A.T .issupportedbytheAmericanCancerSociety(RSG-15-189-01-RMC), St. Baldrick\u2019s Foundation (581357), NCI/NIH P01CA229086, and NCI/NIH R01CA252239. W ewouldliketothanktheAppliedBioinformaticsLaboratories(ABL)forproviding bioinformaticssupportandhelpingwiththeanalysisandinterpretationofthedata.ABLare supportedbytheCancerCenterSupportGrantP30CA016087attheLauraandIsaacPerlmutter Cancer Center. This work has used computing resources at the NYU School of Medicine High PerformanceComputingFa cility .V .S issupportedbyFondazioneAssociazioneItalianaperla RicercasulCancro(AIRC,MFAG2018,ID.21771).ThisworkwasalsosupportedbytheMayo ClinicCenterforIndividualizedMedicineandtheDepartmentofExperimentalPathologyand LaboratoryMedicine,MayoClinicNationalCancerInstitute-designatedComprehensiveCancer CenterOvarianSPOREgrant(CareerDevelopmentA wardP50CA136393)toA.G.-M.Author contributions:Q.J.designedthestudy,performedandinterpretedmostoftheexperiments, andwrotethemanuscript.B.G.D.designedthestudy,performedandinterpretedexperiments, and wrote the manuscript. P .N. conceived and designed the study, directed research, interpretedexperiments,andwrotethemanuscript.Y .Z. performedandhelpedwith bioinformaticsanalysis.S.N.andA.T .performedbioinformaticsanalysisofA T A C-seq, Hi-C,RNA-seq,anddataintegrationandwrotethemanuscript.C.H.helpedwithdrugsynergystudies.V .S., G.V ., andG.B.performedandanalyzedtheRPPAstudiesandpatientsamplestudies.Q.J.,L.S., I.K.,M.P ., andB.G.D.performedorhelpedwiththeinvivostudies.G.Y .andI.B.-S.performedor helpedwiththeexperiments.I.D.providedtheUSP11peptide.A.G.-M.andS.L.S.performed A T A C-seq experiments.Y .-C.T ., andB.B.performedprimarypatientsamplestudies.P .K.S. helped withimmunofluorescenceanalysis.B.-K.C.andY .A.G. performedandanalyzedproteomicsdata. C.B.andJ.V .L. performedandinterpretedchromatinimmunoprecipitationstudies,cellculture experiments,andbiochemicalstudies.P .V .V .andJ.D.C.designedandhelpedwithexecutionof xenograftexperimentsandwrotethemanuscript.W .V .L. performedbioinformaticsanalysisof PeCandata.I.F .performedbioinformaticsanalysis,helpedwithdesignofexperiments,and performedexperiments.T .P .designed,performedstudiesandinterpreteddata,handledand analyzedprimarysamples,analyzedpubliclyavailabledata,andwrotethemanuscript. Competinginterests:Theauthorsdeclarethattheyhav enocompetinginterests.Dataand materialsavailability:SequencingdatacreatedinthisstudyaredepositedintheGene ExpressionOmnibus(GEO;https://ncbi.nlm.nih.gov/geo/;accessionnumberGSE182683).The rawfilesforourproteomicsstudiesaredepositedinMassIVE(MSV000088930;https://massive. ucsd.edu/ProteoSAFe/dataset.jsp?task=d91ad55338bc4c7297744cb321a3c928).Alldata neededtoevaluatetheconclusionsinthepaperarepresentinthepaperand/orthe SupplementaryMaterials.Biologicalmaterialusedinthisstudycanbeobtainedfromthe authors upon request. There were no custom codes used in our manuscript. Previously publishedbioinformaticsalgorithmswereusedasdescribedinMethods.Plasmidsexpressing wild-typeandcatalyticallyinactiveUSP7andUSP11proteinscanbeprovidedbyAddgene pending scientific reviewand a completed material transfer agreement. Requests for these plasmidsshouldbesubmittedtoAddgeneandmta@addgene.org.TheUsp11knockoutmouse strain(em08053;http://informatics.jax.org/allele/MGI:4419682)canbeprovidedbythe W ellcome Trust Sanger Institute pending scientific review and a completed material transfer agreement.RequestsforthismousestrainsshouldbesubmittedtoSangerInstituteand [email protected].
ASJC Scopus subject areas
- General
