2023
CD25 recruits inhibitory phosphatases for feedback control of B-cell receptor signaling
Sun R, Lee J, Robinson M, Kume K, Cosgun K, Chan L, Leveille E, Geng H, Vykunta V, Shy B, Marson A, Meffre E, Müschen M. CD25 recruits inhibitory phosphatases for feedback control of B-cell receptor signaling. The Journal Of Immunology 2023, 210: 154.23-154.23. DOI: 10.4049/jimmunol.210.supp.154.23.Peer-Reviewed Original ResearchAntigen-experienced B cellsB cellsEarly B cell developmentGerminal centersB cell developmentSpontaneous germinal centersCD25 surface expressionAutoreactive B cellsRole of CD25B cell toleranceB-cell receptor signalingB-cell leukemiaB cell receptorAutoantibody productionCD25Cell toleranceGenetic ablationReceptor signalingBCR signalingOncogenic signalingInhibitorySuccessful initiationSignalingNegative selectionAutoimmunity
2022
SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies
Leveille E, Chan LN, Mirza AS, Kume K, Müschen M. SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies. Cellular Signalling 2022, 94: 110331. PMID: 35398488, DOI: 10.1016/j.cellsig.2022.110331.Peer-Reviewed Original ResearchConceptsChronic lymphocytic leukemiaB-cell malignanciesT cell receptorB cell receptorB-cell chronic lymphocytic leukemiaPathological B-cellsPoor clinical outcomeAcute lymphoblastic leukemiaExpression of SykT lymphocyte developmentClinical outcomesAggressive diseaseActivation of NFATAutoimmune diseasesLymphoblastic leukemiaT lymphocytesLymphocytic leukemiaCell lymphomaLymphoid malignanciesB cellsPI3K-pathwayOncogenic driversMalignancyNegative selectionPremalignant cells
2021
Identification of a Conserved Intracellular Loop (CIL) Structure That Scaffolds PIP3 to Amplify Oncogenic Signaling during Malignant B-Cell Transformation
Lee J, Robinson M, Ma N, Sadras T, Cosgun K, Chan L, Kume K, Thomas-Tikhonenko A, Weinstock D, Diamond M, Vaidehi N, Müschen M. Identification of a Conserved Intracellular Loop (CIL) Structure That Scaffolds PIP3 to Amplify Oncogenic Signaling during Malignant B-Cell Transformation. Blood 2021, 138: 868. DOI: 10.1182/blood-2021-149646.Peer-Reviewed Original ResearchLipid raftsB cell receptorB cell activationB cell activation signalsConstitutive membrane localizationMalignant B-cell transformationPleckstrin homology domainCell membrane lipid compositionMembrane lipid compositionNormal B-cell activationEndosomal proteinCell membrane lipidsBasic lysine residueHomology domainPH domainMembrane localizationB-cell transformationProteomic analysisEndosomal membranesPIP3PIP3 accumulationOncogenic signalingOncogenic transformationGene expressionInducible activationPharmacological Targeting of PI3K-Dependent Central Tolerance Mechanisms in Refractory Pre-Germinal Center B-Cell Malignancies
Kume K, Lee J, Chan L, Robinson M, Cosgun K, Meffre E, Müschen M. Pharmacological Targeting of PI3K-Dependent Central Tolerance Mechanisms in Refractory Pre-Germinal Center B-Cell Malignancies. Blood 2021, 138: 2267. DOI: 10.1182/blood-2021-149806.Peer-Reviewed Original ResearchCentral tolerance mechanismsMantle cell lymphomaB-cell malignanciesAutoreactive B cellsB cellsB cell developmentB cell receptorEarly B cell developmentB-ALLClinical cohortPharmacological targetingPathological signalingU-CLLNormal B-cell activationAutoreactive B cell receptorsRefractory B-ALLSequential treatment regimensPI3KNegative B cell selectionChronic lymphocytic leukemiaLarge clinical cohortB cell activationB-cell tumorsHuman B lymphopoiesisB cell selection
2019
Autonomous Ca2+ Oscillations Reflect Oncogenic Signaling in B-ALL Cells
Kume K, Chen L, Lee J, Müschen M. Autonomous Ca2+ Oscillations Reflect Oncogenic Signaling in B-ALL Cells. Blood 2019, 134: 1253. DOI: 10.1182/blood-2019-130708.Peer-Reviewed Original ResearchBCR-ABL1Stromal interaction molecule 1Activation of NFATc1B cell receptorOncogenic kinase activityAutonomous Ca2Oncogenic signalingB cellsOscillatory Ca2Deletion of Stim1Poor clinical outcomeBCR-ABL1 kinase activityRole of SOCENormal B cellsCre-mediated deletionStrong cytotoxic responseStore-operated Ca2B cell survivalOncogenic kinasesClinical outcomesHodgkin's lymphomaB-ALLPump inhibitorsMouse modelKinase activitySignaling Input from Divergent Pathways Subverts Malignant B-Cell Transformation
Chan L, Murakami M, Caesar R, Hurtz C, Kume K, Sadras T, Shojaee S, Pölönen P, Ugale A, Lee J, Cosgun K, Geng H, Heinäniemi M, Lohi O, Wiita A, Izraeli S, Weinstock D, Müschen M. Signaling Input from Divergent Pathways Subverts Malignant B-Cell Transformation. Blood 2019, 134: 3944. DOI: 10.1182/blood-2019-130774.Peer-Reviewed Original ResearchB-cell transformationPrincipal oncogenic driverMalignant B-cell transformationOncogenic driversMalignant transformationNormal B cellsDrug-resistant cancersCentral oncogenic driverCurrent treatmentB cellsPharmacological reactivationSingle oncogenic pathwaySmall molecule agonistsSurface receptorsAdvisory CommitteeB cell receptorERK signal pathwayNormal B cell developmentTreatment responseRare caseDivergent signaling pathwaysSolid tumorsB cell developmentFatal diseaseMolecule agonistsDynamic Assembly of a Feedback Complex to Regulate Oncogenic B-Cell Receptor-Signaling
Lee J, Kume K, Chen Z, Xiao G, Cosgun K, Chen L, Chan L, Klemm L, Chen C, Ma N, Chan W, Forman S, Zammarchi F, Van Berkel P, Melnick A, Ngo V, Geng H, Luger S, Litzow M, McManus M, Vaidehi N, Paietta E, Meffre E, Weinstock D, Müschen M. Dynamic Assembly of a Feedback Complex to Regulate Oncogenic B-Cell Receptor-Signaling. Blood 2019, 134: 393. DOI: 10.1182/blood-2019-131270.Peer-Reviewed Original ResearchB-cell malignanciesB-cell leukemiaB cell receptorPoor clinical outcomeTransplant recipientsB cellsCytoplasmic tailClinical outcomesADC therapeuticsFatal diseaseProximity-dependent biotin identificationRefractory B-cell malignanciesPatient-derived xenograft modelsT cell growth factorNormal B cell developmentClinical outcome dataShort cytoplasmic tailHomology-directed repairB-cell receptor signalingCell membrane translocationNF-κB activationInterleukin-2 (IL-2) functionB cell developmentB-cell tumorsGenetic mouse modelsMetabolic 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 topologyCD25-Dependent Feedback Control of the B-Cell Receptor and Its Oncogenic Mimics in B-Cell Malignancies
Lee J, Kume K, Chen Z, Xiao G, Cosgun K, Chan L, Chen C, Pillai R, Chan W, Forman S, Kwak L, Zammarchi F, Van Berkel P, Weinstock D, Melnick A, Ngo V, Geng H, Luger S, Litzow M, Belot A, Uzel G, McManus M, Paietta E, Meffre E, Muschen M. CD25-Dependent Feedback Control of the B-Cell Receptor and Its Oncogenic Mimics in B-Cell Malignancies. Blood 2018, 132: 776. DOI: 10.1182/blood-2018-99-117553.Peer-Reviewed Original ResearchB cell receptorReceptor chainsB-cell malignanciesNormal B cell developmentT cell receptor signalingB-cell leukemiaHomology-directed repairCell membrane translocationPoor clinical outcomeB cell developmentFeedback regulatorTransplant recipientsNegative feedback regulatorNegative feedback regulationCytoplasmic tailClinical outcomesGene expressionMolecule downstreamCytokine receptor chainsBCR signalingT cellsB cell selectionGenetic mouse modelsProliferation signalsAstra ZenecaDUSP1/6 Inhibition Reduces Tumor Cells and Activates Immune Response in Chronic Lymphocytic Leukemia
Braun M, Ecker V, Neumayer T, Muschen M, Ruland J, Buchner M. DUSP1/6 Inhibition Reduces Tumor Cells and Activates Immune Response in Chronic Lymphocytic Leukemia. Blood 2018, 132: 2857. DOI: 10.1182/blood-2018-99-117052.Peer-Reviewed Original ResearchPatient-derived peripheral blood mononuclear cellsChronic lymphocytic leukemiaMyeloid-derived suppressor cellsB cell receptorImmunogenic cell deathCLL cellsPrimary CLL cellsB cellsImmune cellsT cellsTreatment optionsImmune responseLymphocytic leukemiaBCI treatmentDonor-derived B cellsAntigen-specific T cell proliferationHematopoietic stem cell transplantationPeripheral blood mononuclear cellsHigh-mobility group box 1 proteinMobility group box 1 proteinCell deathGroup box 1 proteinHyperphosphorylation of ERK1/2Poor-risk diseaseCD8 T cells
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
2015
Targeted Activation of B Cell Autoimmunity Checkpoints in Acute Lymphoblastic Leukemia
Chen Z, Geng H, Lowell C, Weiss A, Hunger S, Melnick A, Muschen M. Targeted Activation of B Cell Autoimmunity Checkpoints in Acute Lymphoblastic Leukemia. Blood 2015, 126: 3716. DOI: 10.1182/blood.v126.23.3716.3716.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsB cell receptorAcute lymphoblastic leukemiaPre-BCR signalingB cellsB cell selectionLymphoblastic leukemiaBCR-ABL1Autoreactive B cell receptorsCell deathPre-B-cell originAcute lymphoblastic leukemia cellsCurrent therapy approachesLeukemia cellsWorse clinical outcomesSelf-reactive B cellsNegative B cell selectionPotent tyrosine kinase inhibitorLymphoblastic leukemia cellsNovel small molecule inhibitorTypes of cancerUbiquitous self-antigenClinical outcomesIncremental increasePoor outcomeExpression of B and T Lymphocyte Attenuator (BTLA) Correlates with CNS Metastasis and Adverse Prognosis in Activated B-Cell Lymphoma and Acute Lymphoblastic Leukemia
Geng H, Chen Z, Anderson S, Fraser E, Lu M, Lingjing C, Collins C, Markus M, Rubenstein J. Expression of B and T Lymphocyte Attenuator (BTLA) Correlates with CNS Metastasis and Adverse Prognosis in Activated B-Cell Lymphoma and Acute Lymphoblastic Leukemia. Blood 2015, 126: 3900. DOI: 10.1182/blood.v126.23.3900.3900.Peer-Reviewed Original ResearchPatient-derived cell linesLarge B-cell lymphomaB-cell lymphomaShorter overall survivalAcute lymphoblastic leukemiaHigh BTLA expressionBTLA expressionOverall survivalHigh-resolution array-based comparative genomic hybridizationMurine modelRecurrent copy number gainsDNA copy number aberrationsArray-based comparative genomic hybridizationCell linesCNS metastasisLymphoblastic leukemiaCopy number gainsB cell receptorComparative genomic hybridizationCopy number aberrationsPrimary central nervous system lymphomaGenomic changesCentral nervous system lymphomaTranscript levelsAggressive B-cell lymphomas
2014
Harnessing Negative B Cell Selection to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia
Chen Z, Shojaee S, Geng H, Lee J, Buchner M, Klemm L, Lowell C, Paietta E, Willman C, Carroll W, Melnick A, Jung J, Jumaa H, Coligan J, Bolland S, Mak T, Muschen M. Harnessing Negative B Cell Selection to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia. Blood 2014, 124: 792. DOI: 10.1182/blood.v124.21.792.792.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaTyrosine kinase inhibitorsB cell receptorInhibitory receptorsTherapeutic targetPre-BCR signalingLymphoblastic leukemiaXenograft cellsB cellsSurvival rateB-cell acute lymphoblastic leukemiaCell deathAuto-reactive clonesFree survival rateCell acute lymphoblastic leukemiaOverall survival rateWorse clinical outcomesLeukemia cellsNegative B cell selectionAdditional therapeutic targetsAvailable therapeutic interventionsG1cell cycle arrestPotent tyrosine kinase inhibitorNovel small molecule inhibitorColony formation capacitySelf-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
Bruton′s Tyrosine Kinase Inhibitor Ibrutinib Interferes With Constitutive and Induced Pre-B Cell Receptor Signaling In B-Cell Acute Lymphoblastic Leukemia
Kim E, Koehrer S, Rosin N, Wang Z, Thomas D, Ravandi F, Kornblau S, Kantarjian H, O'Brien S, Estrov Z, Buggy J, Muschen M, Davis R, Burger J. Bruton′s Tyrosine Kinase Inhibitor Ibrutinib Interferes With Constitutive and Induced Pre-B Cell Receptor Signaling In B-Cell Acute Lymphoblastic Leukemia. Blood 2013, 122: 1399. DOI: 10.1182/blood.v122.21.1399.1399.Peer-Reviewed Original ResearchB cell receptorBruton's tyrosine kinasePre-BCR signalingInhibitor ibrutinibCalcium mobilizationCell linesBruton tyrosine kinase inhibitor ibrutinibB-cell acute lymphoblastic leukemiaGene expression profile analysisB-cell acute lymphoblastic leukemia cell linesEffects of ibrutinibAcute lymphoblastic leukemia cell lineAcute lymphoblastic leukemiaCell proliferationKinase inhibitor ibrutinibIntracellular calcium mobilizationLymphoblastic leukemia cell lineBTK inhibitor ibrutinibCalcium flux assaysB cell activationPre-B cell receptor signalingHalf maximal inhibitory concentrationV4 Expression BeadChipSensitive cell linesTyrosine kinaseInhibitory Receptors and Phosphatases Enable Oncogenic Tyrosine Kinase Signaling In B Cell Lineage Leukemia
Chen Z, Shojaee S, Geng H, Lee J, Buchner M, Klemm L, Lowell C, Paietta E, Willman C, Carroll W, Melnick A, Jung J, Jumaa H, Coligan J, Bolland S, Mak T, Muschen M. Inhibitory Receptors and Phosphatases Enable Oncogenic Tyrosine Kinase Signaling In B Cell Lineage Leukemia. Blood 2013, 122: 229. DOI: 10.1182/blood.v122.21.229.229.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaB cell receptorTyrosine kinase inhibitorsInhibitory receptorsTherapeutic targetB cellsBCR-ABL1Survival rateB-cell lineage leukemiaCell deathAuto-reactive clonesFree survival rateLeukemia cellsOverall survival rateWorse clinical outcomesG0/G1 cell cycle arrestAdditional therapeutic targetsCycle arrestAvailable therapeutic interventionsG1cell cycle arrestPotential therapeutic targetG1 cell cycle arrestOncogenic tyrosine kinasesNovel small molecule inhibitorCellular senescence
2006
SLP65 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 replacementDeficiencyExpressionThe 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