2020
IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells
Lee J, Robinson ME, Ma N, Artadji D, Ahmed MA, Xiao G, Sadras T, Deb G, Winchester J, Cosgun KN, Geng H, Chan LN, Kume K, Miettinen TP, Zhang Y, Nix MA, Klemm L, Chen CW, Chen J, Khairnar V, Wiita AP, Thomas-Tikhonenko A, Farzan M, Jung JU, Weinstock DM, Manalis SR, Diamond MS, Vaidehi N, Müschen M. IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells. Nature 2020, 588: 491-497. PMID: 33149299, PMCID: PMC8087162, DOI: 10.1038/s41586-020-2884-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CD19B-LymphocytesCell Transformation, NeoplasticFemaleGerminal CenterHumansIntegrinsMembrane MicrodomainsMembrane ProteinsMiceMice, Inbred C57BLMice, Inbred NODModels, MolecularPhosphatidylinositol 3-KinasesPhosphatidylinositol PhosphatesPhosphorylationReceptors, Antigen, B-CellRNA-Binding ProteinsSignal TransductionConceptsPI3KCell leukemiaAntiviral effector functionsAntigen-specific antibodiesInterferon-induced transmembrane proteinsIFITM3 functionDevelopment of leukemiaCell surfacePoor outcomeOncogenic PI3KClinical cohortEffector functionsGerminal centersMouse modelB cellsExpression of IFITM3Malignant transformationAccumulation of PIP3PI3K signalsCell receptorNormal numbersLeukemiaDefective expressionEndosomal proteinIFITM3Signalling 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
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 4Metabolic gatekeeper function of B-lymphoid transcription factors
Chan LN, Chen Z, Braas D, Lee JW, Xiao G, Geng H, Cosgun KN, Hurtz C, Shojaee S, Cazzaniga V, Schjerven H, Ernst T, Hochhaus A, Kornblau SM, Konopleva M, Pufall MA, Cazzaniga G, Liu GJ, Milne TA, Koeffler HP, Ross TS, Sánchez-García I, Borkhardt A, Yamamoto KR, Dickins RA, Graeber TG, Müschen M. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 2017, 542: 479-483. PMID: 28192788, PMCID: PMC5621518, DOI: 10.1038/nature21076.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesAnimalsB-LymphocytesCarcinogenesisCarrier ProteinsCell DeathChromatin ImmunoprecipitationCitric Acid CycleDisease Models, AnimalEnergy MetabolismFemaleGene Expression Regulation, NeoplasticGlucocorticoidsGlucoseHumansIkaros Transcription FactorMiceMice, TransgenicPAX5 Transcription FactorPrecursor B-Cell Lymphoblastic Leukemia-LymphomaProtein Serine-Threonine KinasesPyruvic AcidReceptor, Cannabinoid, CB2Receptors, GlucocorticoidSequence Analysis, RNATranscription Factors
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 potencyBiology
2015
Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia
Swaminathan S, Klemm L, Park E, Papaemmanuil E, Ford A, Kweon SM, Trageser D, Hasselfeld B, Henke N, Mooster J, Geng H, Schwarz K, Kogan SC, Casellas R, Schatz DG, Lieber MR, Greaves MF, Müschen M. Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nature Immunology 2015, 16: 766-774. PMID: 25985233, PMCID: PMC4475638, DOI: 10.1038/ni.3160.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAnimalsAntibody DiversityB-LymphocytesChildChild, PreschoolClonal EvolutionCytidine DeaminaseDNA-Binding ProteinsFemaleFlow CytometryHomeodomain ProteinsHumansImmunoblottingInfantMaleMice, Inbred NODMice, KnockoutMice, SCIDMice, TransgenicMicroscopy, FluorescencePrecursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidReverse Transcriptase Polymerase Chain ReactionTumor Cells, CulturedSignalling 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
2005
Mimicry 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
2004
The BCR-ABL1 Kinase Bypasses Selection for the Expression of a Pre–B Cell Receptor in Pre–B Acute Lymphoblastic Leukemia Cells
Klein F, Feldhahn N, Harder L, Wang H, Wartenberg M, Hofmann WK, Wernet P, Siebert R, Müschen M. The BCR-ABL1 Kinase Bypasses Selection for the Expression of a Pre–B Cell Receptor in Pre–B Acute Lymphoblastic Leukemia Cells. Journal Of Experimental Medicine 2004, 199: 673-685. PMID: 14993251, PMCID: PMC2213306, DOI: 10.1084/jem.20031637.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdolescentAdultAgedBase SequenceCarrier ProteinsChildChild, PreschoolDNA, NeoplasmFemaleFusion Proteins, bcr-ablGene ExpressionGene Rearrangement, B-Lymphocyte, Heavy ChainHumansMaleMembrane GlycoproteinsMiddle AgedPhosphoproteinsPre-B Cell ReceptorsPrecursor B-Cell Lymphoblastic Leukemia-LymphomaProtein-Tyrosine KinasesReceptors, Antigen, B-CellSelection, GeneticConceptsPre-B cell receptorVH region genesWide gene expression profilesPre-B cell receptor signalingFunctional B-cell receptorFunctional pre-B cell receptorCell receptorReceptor engagementAntigen receptor engagementLeukemia cellsCell receptor signalingGene expression profilesRegion genesCell receptor engagementBCR-ABL1 kinase activityB cell receptorImmature B cellsVH gene rearrangementsKinase activityGene expressionExpression profilesAcute lymphoblastic leukemiaReceptor signalingSerial analysisBCR-ABL1
2001
Resistance to CD95‐mediated apoptosis in breast cancer is not due to somatic mutation of the CD95 gene
Müschen M, Re D, Betz B, Moers C, Wolf J, Niederacher D, Diehl V, Beckmann M. Resistance to CD95‐mediated apoptosis in breast cancer is not due to somatic mutation of the CD95 gene. International Journal Of Cancer 2001, 92: 309-310. PMID: 11291062, DOI: 10.1002/1097-0215(200102)9999:9999<::aid-ijc1188>3.0.co;2-5.Peer-Reviewed Original ResearchMolecular Single-Cell Analysis of Hodgkin- and Reed-Sternberg Cells Harboring Unmutated Immunoglobulin Variable Region Genes
Müschen M, Küppers R, Spieker T, Bräuninger A, Rajewsky K, Hansmann M. Molecular Single-Cell Analysis of Hodgkin- and Reed-Sternberg Cells Harboring Unmutated Immunoglobulin Variable Region Genes. Laboratory Investigation 2001, 81: 289-295. PMID: 11310822, DOI: 10.1038/labinvest.3780237.Peer-Reviewed Original ResearchConceptsImmunoglobulin variable region genesRegion genesVariable region genesGerminal center B cellsSomatic mutationsFounder cellsGerminal center founder cellsB cellsGenesIntrinsic propensityClonal progenyUnmutated immunoglobulin variable region genesClassical Hodgkin's diseaseAntigen-experienced B cellsCell analysisRS cellsMutationsNaive B cellsReed-Sternberg cellsCellsB-lineageLineagesProgenyClonesApoptosis
2000
Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells.
Müschen M, Re D, Bräuninger A, Wolf J, Hansmann M, Diehl V, Küppers R, Rajewsky K. Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells. Cancer Research 2000, 60: 5640-3. PMID: 11059754.Peer-Reviewed Original ResearchCD95 ligand expression as a criterion of malignant transformation in breast cancer
Müschen M, Beckmann M. CD95 ligand expression as a criterion of malignant transformation in breast cancer. The Journal Of Pathology 2000, 191: 468-469. PMID: 10918226, DOI: 10.1002/1096-9896(200008)191:4<468::aid-path647>3.0.co;2-j.Peer-Reviewed Original ResearchCD95 ligand expression as a mechanism of immune escape in breast cancer
Müschen M, Moers C, Warskulat U, Even J, Niederacher D, Beckmann M. CD95 ligand expression as a mechanism of immune escape in breast cancer. Immunology 2000, 99: 69-77. PMID: 10651943, PMCID: PMC2327134, DOI: 10.1046/j.1365-2567.2000.00921.x.Peer-Reviewed Original ResearchMeSH KeywordsApoptosisBreast NeoplasmsCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesEnzyme-Linked Immunosorbent AssayFas Ligand ProteinFas ReceptorFemaleFlow CytometryHumansImmunohistochemistryJurkat CellsLymphocyte CountMembrane GlycoproteinsProtein IsoformsReverse Transcriptase Polymerase Chain ReactionRNA, MessengerConceptsBreast cancer cellsT cellsBreast cancerCD95L expressionImmune escapeIFN-gammaCancer cellsJurkat T cellsTumor-infiltrating T cellsCD95L mRNA levelsDepletion of CD4Cultured breast cancer cellsBreast cancer patientsPeripheral blood lymphocytesCD95/CD95L systemBreast cancer cell linesNon-malignant mammary tissuesActivated T cellsCD95 ligand expressionRate of apoptosisBreast cancer sectionsCancer cell linesInteraction of CD95Systemic immunosuppressionCancer patients
1999
CD95 ligand expression in dedifferentiated breast cancer
Müschen M, Moers C, Warskulat U, Niederacher D, Betz B, Even J, Lim A, Josien R, Beckmann M, Häussinger D. CD95 ligand expression in dedifferentiated breast cancer. The Journal Of Pathology 1999, 189: 378-386. PMID: 10547600, DOI: 10.1002/(sici)1096-9896(199911)189:3<378::aid-path439>3.0.co;2-d.Peer-Reviewed Original ResearchConceptsReverse transcriptase-polymerase chain reactionBreast cancerCD95 ligand expressionMRNA levelsLigand expressionGrade III breast cancerMammary tissueCD95L mRNA levelsTumor-infiltrating lymphocytesCD95 ligandHigh-grade carcinomaQuantitative reverse transcriptase-polymerase chain reactionBenign mammary tissuesTissue sectionsBreast cancer tissuesNon-malignant mammary tissuesTranscriptase-polymerase chain reactionBreast cancer tissue sectionsBreast cancer sectionsCancer tissue sectionsGrade IGrade IIHistopathological gradingReceptor expressionCancer tissuesInvolvement of Soluble CD95 in Churg-Strauss Syndrome
Müschen M, Warskulat U, Perniok A, Even J, Moers C, Kismet B, Temizkan N, Simon D, Schneider M, Häussinger D. Involvement of Soluble CD95 in Churg-Strauss Syndrome. American Journal Of Pathology 1999, 155: 915-925. PMID: 10487849, PMCID: PMC1866905, DOI: 10.1016/s0002-9440(10)65191-7.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedApoptosisCell SurvivalCells, CulturedChurg-Strauss SyndromeClone CellsCulture Media, ConditionedEnzyme-Linked Immunosorbent AssayEosinophilsFas Ligand ProteinFas ReceptorFemaleGenes, T-Cell Receptor betaHumansImmunosuppressive AgentsMaleMembrane GlycoproteinsMiddle AgedMultigene FamilyReceptors, Tumor Necrosis FactorReverse Transcriptase Polymerase Chain ReactionRNA, MessengerT-LymphocytesConceptsChurg-Strauss syndromeSoluble CD95CSS patientsOligoclonal T cell expansionTCR Vbeta gene usageAutoimmune lymphoproliferative disordersVbeta gene usageRole of eosinophilsT cell expansionPeripheral blood lymphocytesT cell clonesSoluble splice variantCD95L-mediated apoptosisCD95 receptor expressionImmunosuppressive therapyClinical improvementCDR3 motifsEffector cellsLymphoproliferative disordersCS patientsBlood lymphocytesReceptor expressionHealthy individualsVbeta genesEosinophilsRegulation of CD95 (APO‐1/ FAS) ligand and receptor expression in squamous‐cell carcinoma by interferon‐γ and cisplatin
Moers C, Warskulat U, Müschen M, Even J, Niederacher D, Josien R, Koldovsky U, Beckmann M, Häussinger D. Regulation of CD95 (APO‐1/ FAS) ligand and receptor expression in squamous‐cell carcinoma by interferon‐γ and cisplatin. International Journal Of Cancer 1999, 80: 564-572. PMID: 9935158, DOI: 10.1002/(sici)1097-0215(19990209)80:4<564::aid-ijc14>3.0.co;2-x.Peer-Reviewed Original ResearchConceptsSquamous cell carcinomaExpression of CD95LPrimary cell linesPrimary squamous cell carcinomaStroma cellsCD95L expressionAddition of CDDPCD95L mRNA levelsTumor-associated immunosuppressionHuman primary cell linesMRNA levelsEffect of cisplatinCell linesCD95 ligand expressionInvasive tumor tissuesAutologous lymphocytesCell carcinomaReceptor expressionSCC cellsSoluble receptorLigand expressionTumor tissueTumor samplesReceptor isoformsInvasion factors
1998
Deranged CD95 system in a case of Churg–Strauss vasculitis
Müschen M, Warskulat U, Häussinger D, Moers C, Simon D, Even J. Deranged CD95 system in a case of Churg–Strauss vasculitis. Gastroenterology 1998, 114: 1351-1352. PMID: 9618660, DOI: 10.1016/s0016-5085(98)70458-5.Peer-Reviewed Original Research