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 proteinIFITM3
2019
Metabolic gatekeepers to safeguard against autoimmunity and oncogenic B cell transformation
Müschen M. Metabolic gatekeepers to safeguard against autoimmunity and oncogenic B cell transformation. Nature Reviews Immunology 2019, 19: 337-348. PMID: 30890785, DOI: 10.1038/s41577-019-0154-3.Peer-Reviewed Original ResearchConceptsB cell receptorAutoreactive B cell receptorsLineage-determining transcription factorsMetabolic gatekeeperMitochondrial ATP productionB-cell transformationTranscription factorsEnergy stressPhosphate pathway activityATP productionCell transformationSmall cytoplasmic volumeCell deathPathway activityB cellsEnergy metabolismCell proliferationCytoplasmic volumeCell receptorGlucose uptakeOncogeneB cell proliferationCellsMetabolic demandsAdditional glucose
2018
IFITM3-Mediated Regulation of Cell Membrane Dynamics Is Essential for Malignant B-Cell Transformation
Lee J, Geng H, Dinson D, Xiao G, Cosgun K, Chan L, Chen Z, Farzan M, Jung J, Wiita A, Muschen M. IFITM3-Mediated Regulation of Cell Membrane Dynamics Is Essential for Malignant B-Cell Transformation. Blood 2018, 132: 552. DOI: 10.1182/blood-2018-99-117472.Peer-Reviewed Original ResearchB cell receptorLipid raftsOncogenic tyrosine kinasesTyrosine kinasePlasma membraneCentral regulatorNormal B-cell receptorType II transmembrane topologyPI3KMalignant B-cell transformationIntracellular N terminusHomotypic cellular aggregationCell membraneCo-receptor CD19Assembly of membraneMRNA levelsLipid raft formationCell membrane dynamicsPotent tumor suppressorDifferent cell typesCholesterol accumulationCell cycle arrestCell receptorEndocytic motifTransmembrane topology
2016
CD25 Enables Oncogenic BCR Signaling and Represents a Therapeutic Target in Refractory B Cell Malignancies
Lee J, Geng H, Chen Z, Klemm L, Cosgun K, Xiao G, Masouleh B, Hurtz C, Parekh S, Kornblau S, Melnick A, Abbas A, Paietta E, Müschen M. CD25 Enables Oncogenic BCR Signaling and Represents a Therapeutic Target in Refractory B Cell Malignancies. Blood 2016, 128: 4088. DOI: 10.1182/blood.v128.22.4088.4088.Peer-Reviewed Original ResearchB-cell malignanciesB-cell tumorsB cell receptorPoor clinical outcomeCell tumorsCell malignanciesClinical outcomesCD25 expressionB-cell leukemiaT cellsClinical cohortCell leukemiaTherapeutic targetB cellsRefractory B-cell malignanciesCell receptorExpression levelsMultiple B-cell malignanciesTumor clonesRegulatory T cellsHigh expression levelsDivergent clinical outcomesBCR signalingHuman B-cell malignanciesB-cell lymphoma cells
2014
Self-Enforcing Feedback Activation Between BCL6 and Tonic Pre-B Cell Receptor Signaling in Acute Lymphoblastic Leukemia
Geng H, Hurtz C, Baumjohann D, Chen Z, Chen W, Ballabio E, Xiao G, Lee J, Deucher A, Qi Z, Huang C, Nahar R, Kweon S, Shojaee S, Chan L, Yu J, Tyner J, Chang B, Kornblau S, Bijl J, Ye B, Paietta E, Melnick A, Roeder R, Hunger S, Loh M, Milne T, Muschen M. Self-Enforcing Feedback Activation Between BCL6 and Tonic Pre-B Cell Receptor Signaling in Acute Lymphoblastic Leukemia. Blood 2014, 124: 284. DOI: 10.1182/blood.v124.21.284.284.Peer-Reviewed Original ResearchPre-BCR expressionB cell receptorInhibition of BCL6Patient-derived preTreatment of patientsMature B-cell lymphomasB-cell lymphomaPre-BCR signalingTCF3-PBX1Cell lymphomaMouse modelCell receptorDeletion of Bcl6Time of diagnosisBCL6 expressionPoor clinical outcomeAcute lymphoblastic leukemiaNovel mouse modelFeedback activationTranscription factor Bcl6Genetic mouse modelsB cell precursorsInhibition of SykHeavy chain expressionLineage-specific deletion
2013
BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint
Swaminathan S, Huang C, Geng H, Chen Z, Harvey R, Kang H, Ng C, Titz B, Hurtz C, Sadiyah MF, Nowak D, Thoennissen GB, Rand V, Graeber TG, Koeffler HP, Carroll WL, Willman CL, Hall AG, Igarashi K, Melnick A, Müschen M. BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. Nature Medicine 2013, 19: 1014-1022. PMID: 23852341, PMCID: PMC3954721, DOI: 10.1038/nm.3247.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBasic-Leucine Zipper Transcription FactorsCell DeathCell DifferentiationCell SurvivalCell Transformation, NeoplasticDNA-Binding ProteinsGene DeletionGene Expression Regulation, LeukemicGreen Fluorescent ProteinsImmunoglobulin mu-ChainsMiceMolecular Sequence DataPAX5 Transcription FactorPre-B Cell ReceptorsPrecursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidProto-Oncogene Proteins c-bcl-6Proto-Oncogene Proteins c-mycRNA, MessengerSTAT5 Transcription FactorTreatment OutcomeTumor Suppressor Protein p53V(D)J Recombination
2011
Pre-B Cell Receptor-Mediated Activation of BCL6 Induces Pre-B Cell Quiescence Through Transcriptional Repression of MYC
Nahar R, Ramezani-Rad P, Mossner M, Duy C, Cerchietti L, Geng H, Jumaa H, Ye B, Melnick A, Muschen M. Pre-B Cell Receptor-Mediated Activation of BCL6 Induces Pre-B Cell Quiescence Through Transcriptional Repression of MYC. Blood 2011, 118: 1406. DOI: 10.1182/blood.v118.21.1406.1406.Peer-Reviewed Original ResearchPre-B cell receptorCell receptorCell cycle exitExit cell cycleInitial proliferative burstAcute lymphoblastic leukemiaCycle exitB cell precursorsPre-B cell receptor signalingInducible activationTranscriptional repressor BCL6Receptor-Mediated ActivationCell receptor signalingInduction of quiescenceLymphoblastic leukemiaCell surface expressionOverexpression of MYCCCND2 expressionCell cycleBcl6-deficient miceMalignant transformationReceptor signalingReceptors resultsCell precursorsReceptorsMechanisms of Ikaros-Mediated Tumor Suppression
Nahar R, Ramezani-Rad P, Dovat S, Buchner M, Graeber T, Muschen M. Mechanisms of Ikaros-Mediated Tumor Suppression. Blood 2011, 118: 408. DOI: 10.1182/blood.v118.21.408.408.Peer-Reviewed Original ResearchPre-B cell receptor signalingPre-B cell receptorCell receptor signalingAbility of IkarosGene expression changesTumor suppressor pathwayTumor suppressionTumor suppressorDephosphorylation eventsReceptor signalingGenetic evidenceSuppressor pathwayAdapter moleculeExpression changesCritical phosphorylation eventsCommon gene expression changesCell receptorTumor-suppressive transcription factorCell cycle exitSimilar gene expression changesComprehensive gene expression analysisARF/p53 pathwayLeukemia cellsBCR-ABL1 kinaseCell cycle progression
2010
IKAROS and BCL6 Limit Pre-B Cell Expansion and Prevent Leukemogenesis Downstream of the Pre-B Cell Receptor
Nahar R, Ramezani-Rad P, Duy C, Dovat S, Ye B, Melnick A, Muschen M. IKAROS and BCL6 Limit Pre-B Cell Expansion and Prevent Leukemogenesis Downstream of the Pre-B Cell Receptor. Blood 2010, 116: 146. DOI: 10.1182/blood.v116.21.146.146.Peer-Reviewed Original ResearchPre-B cell receptorCell cycle arrestCell cycle progressionTumor suppressorCycle arrestTumor suppressionIkaros functionCycle progressionNegative cell cycle regulationSignaling leadsDephosphorylation of STAT5Cell receptorIkaros expressionBCL6 transcriptional repressorGenome-wide ChIPPre-B cell expansionCell cycle regulationSubsequent cell cycle arrestCentral mediatorOverexpression of MYCProliferation downstreamTranscriptional repressionGenetic experimentsTranscriptional repressorTranscriptional activationMechanisms of Pre-B Cell Receptor-Inactivation In Acute Lymphoblastic Leukemia
Duy C, Nowak D, Klemm L, Nahar R, Ng C, Elliott E, Hofmann W, Heisterkamp N, Lowell C, Koeffler P, Muschen M. Mechanisms of Pre-B Cell Receptor-Inactivation In Acute Lymphoblastic Leukemia. Blood 2010, 116: 147. DOI: 10.1182/blood.v116.21.147.147.Peer-Reviewed Original ResearchPre-B cell receptorImmunoglobulin μ chainCell receptor functionCell receptor stimulationTyrosine kinasePAX5 fusion genesSystematic gene expression analysisΜ chainsSplice variantsCell receptorRapid cell cycle arrestExon 16Immunoglobulin gene rearrangementsReceptor functionReceptor signal transductionPre-B cell receptor functionGene rearrangementsGene expression analysisLeukemia cellsDominant-negative waySyk tyrosine kinaseCell cycle arrestPre B cellsSH2 domainMRNA splicingPre-B Cell Receptor Signaling Distinguishes E2A-PBX1 From Other Subtypes of Acute Lymphoblastic Leukemia
Nahar R, Trageser D, Klemm L, Duy C, Hofmann W, Park E, Kim Y, Heisterkamp N, Jumaa H, Muschen M. Pre-B Cell Receptor Signaling Distinguishes E2A-PBX1 From Other Subtypes of Acute Lymphoblastic Leukemia. Blood 2010, 116: 274. DOI: 10.1182/blood.v116.21.274.274.Peer-Reviewed Original ResearchPre-B cell receptorPre-B cell receptor signalingFunctional pre-B cell receptorEarly pre-B cell stageCanonical Wnt/β-catenin signalingPre-B cell stageCell receptor signalingWnt/β-catenin signalingCell receptor functionE2A-PBX1Β-catenin signalingBCR-ABL1 oncogeneCell stageB cell lineage commitmentCell receptorReceptor signalingPre-B cell receptor expressionEarly B cell developmentComparative gene expressionMLL-AF4Pre-B cell receptor functionCell lineage commitmentReceptor functionGene expression differencesCanonical Wnt/β-cateninSYK Is a Tumor Suppressor In Pre-B Cell Acute Lymphoblastic Leukemia and Not a Therapeutic Target
Ng C, Nahar R, Elliott E, Lowell C, Muschen M. SYK Is a Tumor Suppressor In Pre-B Cell Acute Lymphoblastic Leukemia and Not a Therapeutic Target. Blood 2010, 116: 4199. DOI: 10.1182/blood.v116.21.4199.4199.Peer-Reviewed Original ResearchDeletion of SykPre-B leukemia cellsAcute lymphoblastic leukemiaPre-B cell receptor functionB-cell lymphomaImatinib treatmentTumor-suppressive effectsRole of SykPre-B cell receptorCell cycle arrestBCR-ABL1Cell receptorCritical survival signalsLeukemia cellsCell receptor signalingLymphoblastic leukemiaCell lymphomaSuppressive effectCycle arrestSyk tyrosine kinaseReceptor functionPre-B-cell acute lymphoblastic leukemiaWestern blotReceptor signalingPre-B cell receptor expression
2009
Inactivation of Pre-B Cell Receptor-Mediated Tumor Suppression by Aberrant Splicing in Ph+ Acute Lymphoblastic Leukemia.
Duy C, Sprangers M, Klemm L, Nahar R, Nowak D, Martinelli G, Hofmann W, Koeffler P, Jumaa H, Müschen M. Inactivation of Pre-B Cell Receptor-Mediated Tumor Suppression by Aberrant Splicing in Ph+ Acute Lymphoblastic Leukemia. Blood 2009, 114: 579. DOI: 10.1182/blood.v114.22.579.579.Peer-Reviewed Original ResearchPre-B cell receptorSH2 domainSplice factorsTumor suppressor functionAberrant splicingSplice variantsPre-B cell receptor signalingSequence analysisSplice siteSplice site mutationExon 16Suppressor functionCell receptorImportant protein domainsFunctional SH2 domainSite mutationSplice site selectionDetailed sequence analysisCell receptor signalingDominant negative effectDownstream effector moleculesCell linesMultiple splice variantsSplicing factorsProtein domains
2008
Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1
Trageser D, Duy C, Klemm L, Gruber T, Nahar R, Park E, Kim Y, Groffen J, Heisterkamp N, Hofmann W, Martinelli G, Williams R, Jumaa H, Muschen M. Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1. Blood 2008, 112: 15. DOI: 10.1182/blood.v112.11.15.15.Peer-Reviewed Original ResearchFunctional pre-B cell receptorAcute lymphoblastic leukemiaBCR-ABL1Pre-B cell receptorCell receptorBone marrowPre-B cell receptor functionTransgenic miceLeukemic transformationLeukemic growthNOD/SCID miceWeight lossLeukemia cellsReceptor selectionTransgenic mouse modelSignificant weight lossPre-B cell receptor signalingBCR-ABL1 expressionSigns of diseaseSurvival signalsEarly B cell developmentLeukemic infiltrationSplenic enlargementCell receptor signalingPeripheral bloodThe Pre-B Cell Receptor Suppresses Leukemogenesis by Censoring MYC Expression.
Nahar R, Trageser D, Klemm L, Duy C, van Essen P, Kim Y, Heisterkamp N, Martinelli G, Hofmann W, Jack H, Jumaa H, Muschen M. The Pre-B Cell Receptor Suppresses Leukemogenesis by Censoring MYC Expression. Blood 2008, 112: 1918. DOI: 10.1182/blood.v112.11.1918.1918.Peer-Reviewed Original ResearchPre-B cell receptorPre-B cell receptor expressionPre-B cell receptor signalingFunctional pre-B cell receptorEarly pre-B cell stagePre-B cell stageCell receptor signalingSubstantial growth advantageB cell precursorsCell stageE2A-PBX1Receptor signalingCell receptorCell precursorsEarly B cell developmentGrowth advantageComparative gene expressionMYC expressionMLL-AF4Cell receptor expressionB cell developmentMYC mRNA levelsHeavy chain locusHigh expression levelsBCR-ABL1 oncogeneAberrant Splicing of the SLP65 SH2 Domain Enables Pre-B Cell Transformation and Compromises the Leukemia-Suppressive Function of the Pre-B Cell Receptor
Duy C, Klemm L, Nahar R, van Essen P, Sprangers M, Kim Y, Park E, Martinelli G, Heisterkamp N, Hofmann W, Jumaa H, Muschen M. Aberrant Splicing of the SLP65 SH2 Domain Enables Pre-B Cell Transformation and Compromises the Leukemia-Suppressive Function of the Pre-B Cell Receptor. Blood 2008, 112: 294. DOI: 10.1182/blood.v112.11.294.294.Peer-Reviewed Original ResearchBCR-ABL1Pre-B cell receptorEarly pre-B cell stageCell receptorPre-B cell stageNOD/SCID miceLeukemia cellsPre-B cell receptor signalingSigns of diseaseSplice variantsEarly B cell developmentLeukemic infiltrationQuantitative RT-PCRCell receptor signalingCell receptor engagementSCID miceBone marrowB cell developmentMalignant transformationPre-B-cell transformationLeukemic growthCell transformationInduction of differentiationGermline mutationsMice
2007
Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1.
Trageser D, Klemm L, Herzog S, Kim Y, Duy C, Hofmann W, Groffen J, Heisterkamp N, Jumaa H, Muschen M. Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1. Blood 2007, 110: 2795. DOI: 10.1182/blood.v110.11.2795.2795.Peer-Reviewed Original ResearchPre-B cell receptorFunctional pre-B cell receptorImmunoglobulin heavy chain locusAcute lymphoblastic leukemiaBCR-ABL1Cell receptorSurvival signalsPre-B cell receptor signalingReceptor selectionEarly B cell developmentBone marrowPre-B cell receptor functionTransgenic miceLeukemic transformationCell receptor signalingRapid cell deathB cell developmentHuman BCR-ABL1Potent tumor suppressorHeavy chain locusPre B cellsSingle-cell PCRTransgenic mouse modelCell receptor functionB cell precursors
2006
The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells
Sprangers M, Feldhahn N, Herzog S, Hansmann M, Reppel M, Hescheler J, Jumaa H, Siebert R, Müschen M. The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells. Oncogene 2006, 25: 5056-5062. PMID: 16568084, DOI: 10.1038/sj.onc.1209510.Peer-Reviewed Original ResearchConceptsB-cell lymphoma cellsB cell receptor engagementCell lymphoma cellsSrc kinase LynCell receptor engagementB cell receptorKinase LynReceptor-induced Ca2Lymphoma cellsCell receptorReceptor engagementB-cell receptor signal transductionSrc family kinase LynB-cell-derived lymphomasSrc kinase activityReceptor signal transductionAcute lymphoblastic leukemiaSrc kinase activationProliferation-related moleculesB-cell lymphoma casesReceptor-dependent Ca2Normal B cellsActivation of survivalSignal transductionRNA interference
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 Interferes with Pre-B Cell Receptor Signal Transduction in B Cell Precursor Leukemia Cells.
Klein F, Feldhahn N, Wernet P, Müschen M. The BCR-ABL1 Kinase Interferes with Pre-B Cell Receptor Signal Transduction in B Cell Precursor Leukemia Cells. Blood 2004, 104: 1894. DOI: 10.1182/blood.v104.11.1894.1894.Peer-Reviewed Original ResearchPre-B cell receptorReceptor signal transductionSignal transductionVH gene rearrangementsBCR-ABL1 kinase activityPre-B cell receptor (pre-BCR) signalsKinase activityGenome-wide gene expressionReceptor engagementSignal transduction cascadeLeukemia cellsCell receptorAntigen receptor engagementReceptor-dependent signal transductionNovel target geneCell receptor signalingBCR-ABL1 kinaseApoptotic cell deathCell receptor signalsGene rearrangementsCell receptor engagementBCR-ABL1B cell receptorImmature B cellsTarget genes