2023
Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1‐EEF1A1 Axis
Li M, Yang L, Chan A, Pokharel S, Liu Q, Mattson N, Xu X, Chang W, Miyashita K, Singh P, Zhang L, Li M, Wu J, Wang J, Chen B, Chan L, Lee J, Zhang X, Rosen S, Müschen M, Qi J, Chen J, Hiom K, Bishop A, Chen C. Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1‐EEF1A1 Axis. Advanced Science 2023, 10: 2206584. PMID: 37075745, PMCID: PMC10265057, DOI: 10.1002/advs.202206584.Peer-Reviewed Original ResearchConceptsProtein translation machineryHistone H4 acetylationOncogenic transcription factorNuA4 histoneChromatin remodelersGene bodiesEpigenetic networksTranslation machineryATPase componentEpigenetic controlTumor progressionCRISPR screensTranscription factorsH4 acetylationEpigenetic dysregulationRUVBL1Oncogenic signalingProtein synthesisPatient-derived samplesMYCPharmacological inhibitionEEF1A1 expressionMultiple cancersNovel opportunitiesDynamic interplay
2021
PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis
Pan L, Hong C, Chan LN, Xiao G, Malvi P, Robinson ME, Geng H, Reddy ST, Lee J, Khairnar V, Cosgun KN, Xu L, Kume K, Sadras T, Wang S, Wajapeyee N, Müschen M. PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2016553118. PMID: 33531346, PMCID: PMC7896313, DOI: 10.1073/pnas.2016553118.Peer-Reviewed Original ResearchConceptsTransplant recipient miceDNA double-strand breaksNormal B cell developmentDouble-strand breaksB cell developmentGenetic deletionB cellsLymphoid transcription factorsGlucose transporter GLUT1Gatekeeper functionGlucose uptakeRecipient miceTranscription factorsSomatic recombinationSynthetic lethalityB-cell acute lymphoblastic leukemiaCell developmentMetabolic gatekeeperRefractory B-ALLDeficient murineCell acute lymphoblastic leukemiaPoor clinical outcomeCell typesAcute lymphoblastic leukemiaGlucose transport
2020
Signalling input from divergent pathways subverts B cell transformation
Chan LN, Murakami MA, Robinson ME, Caeser R, Sadras T, Lee J, Cosgun KN, Kume K, Khairnar V, Xiao G, Ahmed MA, Aghania E, Deb G, Hurtz C, Shojaee S, Hong C, Pölönen P, Nix MA, Chen Z, Chen CW, Chen J, Vogt A, Heinäniemi M, Lohi O, Wiita AP, Izraeli S, Geng H, Weinstock DM, Müschen M. Signalling input from divergent pathways subverts B cell transformation. Nature 2020, 583: 845-851. PMID: 32699415, PMCID: PMC7394729, DOI: 10.1038/s41586-020-2513-4.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesCell Line, TumorCell Transformation, NeoplasticEnzyme ActivationExtracellular Signal-Regulated MAP KinasesFemaleHumansLeukemia, B-CellMiceProtein Tyrosine Phosphatase, Non-Receptor Type 6Proto-Oncogene Proteins c-bcl-6Proto-Oncogene Proteins c-mycSignal TransductionSTAT5 Transcription FactorConceptsPre-B cell receptorPrincipal oncogenic driverDivergent pathwaysSignal transduction proteinsPro-B cell stageSingle-cell mutationTranscription factor MYCOncogenic driversDivergent signaling pathwaysSingle oncogenic pathwayCentral oncogenic driverMore mature cellsGenetic reactivationTranscriptional programsB-cell transformationProtein kinasePathway componentsERK activationIndividual mutationsOncogenic STAT5Signaling pathwaysCell transformationCytokine receptorsGenetic lesionsDivergent circuits
2018
B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies
Xiao G, Chan LN, Klemm L, Braas D, Chen Z, Geng H, Zhang QC, Aghajanirefah A, Cosgun KN, Sadras T, Lee J, Mirzapoiazova T, Salgia R, Ernst T, Hochhaus A, Jumaa H, Jiang X, Weinstock DM, Graeber TG, Müschen M. B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies. Cell 2018, 173: 470-484.e18. PMID: 29551267, PMCID: PMC6284818, DOI: 10.1016/j.cell.2018.02.048.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesCarbonCell Line, TumorCell SurvivalGlucoseGlucosephosphate DehydrogenaseGlycolysisHumansIkaros Transcription FactorMiceMice, Inbred C57BLMice, Inbred NODOxidative StressPAX5 Transcription FactorPentose Phosphate PathwayPrecursor Cell Lymphoblastic Leukemia-LymphomaProtein Phosphatase 2Proto-Oncogene Proteins c-bcl-2Transcription, GeneticConceptsPentose phosphate pathwayCarbon utilizationSerine/threonine protein phosphatase 2AB-cell transcription factor PAX5Transcription factor Pax5Favor of glycolysisSmall molecule inhibitionPhosphatase 2ATranscriptional repressionRedox homeostasisOncogenic transformationTumor suppressorMolecule inhibitionPP2AGenetic studiesPhosphate pathwayB cell activationEssential roleB-cell malignanciesCell malignanciesB cellsAntioxidant protectionOxidative stressB-cell tumorsCell activation
2017
Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia
Takao S, Chien W, Madan V, Lin D, Ding L, Sun Q, Mayakonda A, Sudo M, Xu L, Chen Y, Jiang Y, Gery S, Lill M, Park E, Senapedis W, Baloglu E, Müschen M, Koeffler H. Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia. Leukemia 2017, 32: 616-625. PMID: 28904384, DOI: 10.1038/leu.2017.281.Peer-Reviewed Original ResearchMeSH KeywordsAcrylamidesAminopyridinesAnimalsAntineoplastic AgentsApoptosisCell Line, TumorCell ProliferationCell SurvivalCytokinesDisease Models, AnimalFemaleHumansMaleMiceNADNicotinamide PhosphoribosyltransferaseP21-Activated KinasesPrecursor B-Cell Lymphoblastic Leukemia-LymphomaSignal TransductionXenograft Model Antitumor AssaysConceptsB-cell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaP21-activated kinase 4Nicotinamide phosphoribosyltransferaseLymphoblastic leukemiaNAMPT inhibitionPatient-derived xenograft murine modelsPrognosis of patientsNicotinamide adenine dinucleotideNovel therapeutic strategiesNicotinic acid supplementationNovel dual inhibitorXenograft murine modelCell growth inhibitionAcid supplementationMurine modelTherapeutic strategiesRate-limiting enzymeCytogenetic abnormalitiesVivo efficacyPatientsNAMPT inhibitorsInhibitory effectDual inhibitorKinase 4Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL
Schjerven H, Ayongaba EF, Aghajanirefah A, McLaughlin J, Cheng D, Geng H, Boyd JR, Eggesbø LM, Lindeman I, Heath JL, Park E, Witte ON, Smale ST, Frietze S, Müschen M. Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL. Journal Of Experimental Medicine 2017, 214: 793-814. PMID: 28190001, PMCID: PMC5339667, DOI: 10.1084/jem.20160049.Peer-Reviewed Original ResearchConceptsTumor suppressor functionHuman BCR-ABL1Target genesSuppressor functionDevelopmental stage-specific expressionGenome-wide chromatinStage-specific expressionWild-type IkarosTumor suppressor geneChromatin compactionIkaros functionGene pathwaysMultiple genesExpression analysisGenetic analysisInducible expressionTumor suppressorGenetic depletionCell surface markers CD34Suppressor geneGenesIkarosBCR-ABL1Cell acute lymphoblastic leukemiaLeukemic growth
2016
Phosphorylation of a constrained azacyclic FTY720 analog enhances anti-leukemic activity without inducing S1P receptor activation
McCracken A, McMonigle R, Tessier J, Fransson R, Perryman M, Chen B, Keebaugh A, Selwan E, Barr S, Kim S, Roy S, Liu G, Fallegger D, Sernissi L, Brandt C, Moitessier N, Snider A, Clare S, Müschen M, Huwiler A, Kleinman M, Hanessian S, Edinger A. Phosphorylation of a constrained azacyclic FTY720 analog enhances anti-leukemic activity without inducing S1P receptor activation. Leukemia 2016, 31: 669-677. PMID: 27573555, PMCID: PMC5332311, DOI: 10.1038/leu.2016.244.Peer-Reviewed Original ResearchConceptsS1P receptor activationAnti-leukemic actionProtein phosphatase 2APro-apoptotic targetsPhosphatase 2ASphingosine kinase 2Efficient phosphorylationGenetic approachesReceptor activationKinase 2Nutrient accessChemical biologyPhosphorylationTight inverse correlationDistinct mechanismsS1P receptorsAnti-leukemic activityNovel therapeutic approachesLeukemia progressionReceptor activityMRNA expressionAnti-leukemic agentsActivationEnhanced potencyBiologyPTEN opposes negative selection and enables oncogenic transformation of pre-B cells
Shojaee S, Chan LN, Buchner M, Cazzaniga V, Cosgun KN, Geng H, Qiu YH, von Minden MD, Ernst T, Hochhaus A, Cazzaniga G, Melnick A, Kornblau SM, Graeber TG, Wu H, Jumaa H, Müschen M. PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nature Medicine 2016, 22: 379-387. PMID: 26974310, PMCID: PMC5178869, DOI: 10.1038/nm.4062.Peer-Reviewed Original Research
2015
Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia
Chen Z, Shojaee S, Buchner M, Geng H, Lee JW, Klemm L, Titz B, Graeber TG, Park E, Tan YX, Satterthwaite A, Paietta E, Hunger SP, Willman CL, Melnick A, Loh ML, Jung JU, Coligan JE, Bolland S, Mak TW, Limnander A, Jumaa H, Reth M, Weiss A, Lowell CA, Müschen M. Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia. Nature 2015, 521: 357-361. PMID: 25799995, PMCID: PMC4441554, DOI: 10.1038/nature14231.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAnimalsAntigens, CDB-LymphocytesCell DeathCell Line, TumorCell Transformation, NeoplasticDisease Models, AnimalDrug Resistance, NeoplasmEnzyme ActivationFemaleFusion Proteins, bcr-ablGene DeletionHumansInositol Polyphosphate 5-PhosphatasesIntracellular Signaling Peptides and ProteinsMiceMice, Inbred NODMice, SCIDPhosphatidylinositol-3,4,5-Trisphosphate 5-PhosphatasesPhosphoric Monoester HydrolasesPlatelet Endothelial Cell Adhesion Molecule-1Precursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidProtein Tyrosine Phosphatase, Non-Receptor Type 6Protein-Tyrosine KinasesReceptors, Antigen, B-CellReceptors, ImmunologicSignal TransductionSyk KinaseTyrosineXenograft Model Antitumor Assays
2006
Immunoglobulin class‐switch recombination occurs in mantle cell lymphomas
Klapper W, Szczepanowski M, Heidorn K, Müschen M, Liedtke S, Sotnikova A, Andersen N, Greeve J, Parwaresch R. Immunoglobulin class‐switch recombination occurs in mantle cell lymphomas. The Journal Of Pathology 2006, 209: 250-257. PMID: 16508921, DOI: 10.1002/path.1961.Peer-Reviewed Original ResearchCD40 AntigensCell Line, TumorCytidine DeaminaseDendritic Cells, FollicularGenes, Immunoglobulin Heavy ChainHumansImmunoglobulin Class SwitchingImmunoglobulin GImmunohistochemistryInterleukin-4Lymphoma, Mantle-CellMutationRecombination, GeneticReverse Transcriptase Polymerase Chain ReactionRNA, MessengerRNA, NeoplasmTranscription, GeneticSLP65 deficiency results in perpetual V(D)J recombinase activity in pre-B-lymphoblastic leukemia and B-cell lymphoma cells
Sprangers M, Feldhahn N, Liedtke S, Jumaa H, Siebert R, Müschen M. SLP65 deficiency results in perpetual V(D)J recombinase activity in pre-B-lymphoblastic leukemia and B-cell lymphoma cells. Oncogene 2006, 25: 5180-5186. PMID: 16636677, DOI: 10.1038/sj.onc.1209520.Peer-Reviewed Original ResearchConceptsLymphoblastic leukemiaRecombinase activityRAG1/2 expressionB-cell lineage leukemiaDouble-strand break eventsLymphoma cellsSecondary genetic aberrationsB-cell lymphomaB-cell lymphoma cellsB-lymphoid malignanciesB-cell malignanciesB cell receptorVH gene rearrangementsMalignant progressionLeukemiaFrequent featureGenetic aberrationsGene rearrangementsCells resultsRearrangement activityLineage leukemiaMalignancyVH replacementDeficiencyExpression
2005
BCR–ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells
Klein F, Feldhahn N, Herzog S, Sprangers M, Mooster J, Jumaa H, Müschen M. BCR–ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells. Oncogene 2005, 25: 1118-1124. PMID: 16205638, DOI: 10.1038/sj.onc.1209133.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAnimalsAntineoplastic AgentsBenzamidesCell Line, TumorCell LineageCell NucleusFusion Proteins, bcr-ablGene Expression ProfilingGene SilencingHumansIkaros Transcription FactorImatinib MesylateMicePiperazinesPrecursor B-Cell Lymphoblastic Leukemia-LymphomaProtein Kinase InhibitorsProtein-Tyrosine KinasesPyrimidinesConceptsLymphoid lineage commitmentLineage commitmentGenome-wide gene expression profilesAberrant splicingLymphoblastic leukemia cellsLeukemia cellsAberrant expressionGene expression profilesNormal B-cell subsetsCell linesPrecursor cell lineLineage identityLineage infidelityTranscription factorsRNA interferenceExpression profilesInducible expressionUndifferentiated phenotypeSplice variantsDefective expressionBCR-ABL1SplicingIk6ExpressionCellsMimicry of a constitutively active pre–B cell receptor in acute lymphoblastic leukemia cells
Feldhahn N, Klein F, Mooster JL, Hadweh P, Sprangers M, Wartenberg M, Bekhite MM, Hofmann WK, Herzog S, Jumaa H, Rowley JD, Müschen M. Mimicry of a constitutively active pre–B cell receptor in acute lymphoblastic leukemia cells. Journal Of Experimental Medicine 2005, 201: 1837-1852. PMID: 15939795, PMCID: PMC2213268, DOI: 10.1084/jem.20042101.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedCalcium SignalingCell Line, TumorCell SurvivalChildChild, PreschoolFemaleGene Expression Regulation, LeukemicHumansMaleMembrane GlycoproteinsMiddle AgedMolecular MimicryPre-B Cell ReceptorsPrecursor Cell Lymphoblastic Leukemia-LymphomaProtein-Tyrosine KinasesReceptors, Antigen, B-CellConceptsBruton's tyrosine kinaseBCR-ABL1Pre-B cell receptorCell receptorFull‐length Bruton tyrosine kinaseSurvival signalsAcute lymphoblastic leukemia cellsLeukemia cellsBCR-ABL1 kinase activityLymphoblastic leukemia cellsDownstream survival signalsBCR-ABL1 kinaseTyrosine kinaseCell receptor engagementKinase activityBypass selectionSTAT5 phosphorylationSrc homology domain 3BTK activityReceptorsAutonomous Ca2Receptor engagementSimilar extentActivation of PLCgamma1Dependent activation