2023
Optogenetic Control of Oncogenic Signaling in B-Cell Malignancies
Kume K, Lee J, Cheng Z, Robinson M, Leveille E, Cosgun K, Chan L, Feng Y, Arce D, Khanduja D, Toomre D, Müschen M. Optogenetic Control of Oncogenic Signaling in B-Cell Malignancies. Blood 2023, 142: 4138. DOI: 10.1182/blood-2023-190926.Peer-Reviewed Original ResearchB-cell malignanciesB-cell lymphomaMature B-cell lymphomasB cell deathB cellsB cell developmentGenetic deletionMantle cell lymphomaNF-kB signalingBCR signal inhibitorsB cell precursorsCell of originCell viabilityChronic active BCRB cell survivalB cell receptor signalsHodgkin's diseaseMultiple myelomaNormal B cell developmentPlasma cellsBtk tyrosine kinaseCell lymphomaBurkitt's lymphomaNF-kBSmall molecule inhibitorsImmunoglobulin Light Chains Control Permissiveness to Malignant B-Cell Transformation By RAS-Pathway Lesions
Chan L, Kume K, Hurtz C, Robinson M, Cosgun K, Müschen M. Immunoglobulin Light Chains Control Permissiveness to Malignant B-Cell Transformation By RAS-Pathway Lesions. Blood 2023, 142: 2974. DOI: 10.1182/blood-2023-190163.Peer-Reviewed Original ResearchJeKo-1 cellsB cell precursorsMature B cellsB cellsMantle cell lymphoma cellsCell lymphoma cellsGenetic ablationImmunoglobulin light chainsRAS activationOncogenic RASMalignant transformationB-cell acute lymphoblastic leukemiaConventional light chainsRAS pathwayLymphoma cellsCell deathOncogenic RAS activationLight chainAcute lymphoblastic leukemiaMature B-cell lymphomasTransgenic mouse modelB-cell lymphomaB-cell malignanciesMalignant B-cell transformationKappa-LCDynamic Recruitment of Inhibitory Complexes Controls Oncogenic Signaling in B-Cell Malignancies
Sun R, Lee J, Robinson M, Kume K, Ma N, Cosgun K, Chan L, Antoshkina I, Khanduja D, Leveille E, Katz S, Chen J, Paietta E, Vaidehi N, Müschen M. Dynamic Recruitment of Inhibitory Complexes Controls Oncogenic Signaling in B-Cell Malignancies. Blood 2023, 142: 719. DOI: 10.1182/blood-2023-189742.Peer-Reviewed Original ResearchB-cell malignanciesB-cell lymphomaHigher serum levelsMature B-cell lymphomasSoluble CD25Serum levelsOncogenic signalingMouse modelB cellsAggressive B-cell lymphomasAcceleration of diseaseActivation of inhibitoryPoor clinical outcomeCD25 surface expressionB cell subsetsRole of CD25Patient-derived xenograftsB cell populationsB-cell receptor signalingB-cell leukemiaGenetic mouse modelsKnockin mouse modelCell deathMature B cell populationClinical outcomes
2021
Pharmacological 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 selectionBeta-Catenin Forms Repressive Complexes with Ikzf1 and Ikzf3 to Orchestrate Tumor-Suppression in B-Cell Malignancies
Cosgun K, Robinson M, Chan L, Hur M, Leveille E, Song J, Chan W, Müschen M. Beta-Catenin Forms Repressive Complexes with Ikzf1 and Ikzf3 to Orchestrate Tumor-Suppression in B-Cell Malignancies. Blood 2021, 138: 29. DOI: 10.1182/blood-2021-148597.Peer-Reviewed Original ResearchB-cell malignanciesΒ-catenin activationΒ-cateninOncogenic Wnt/β-catenin signalingMalignant B-lymphoid cellsGenetic deletionRefractory B-ALLTranscriptional repressionB-cell lymphomaTumor suppressionWnt/β-catenin signalingΒ-catenin/TCF complexMature B-cell malignanciesB-lymphoid cellsCancer cell linesΒ-catenin signalingClonal fitnessOverall survivalLeukemia burdenNSG miceB-ALLCell cycle arrestNuclear β-cateninPan-cancer analysisFrequent lesions
2019
Dynamic 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 modelsIfitm3 Is Essential for PI(3,4,5)P3-Dependent B-Cell Activation and Leukemogenesis
Lee J, Xiao G, Cosgun K, Geng H, Ma N, Chan L, Kume K, Nix M, Chen Z, Chen C, Chen J, Khairnar V, Wiita A, Thomas-Tikhonenko A, Farzan M, Diamond M, Jung J, Vaidehi N, Müschen M. Ifitm3 Is Essential for PI(3,4,5)P3-Dependent B-Cell Activation and Leukemogenesis. Blood 2019, 134: 2782. DOI: 10.1182/blood-2019-127615.Peer-Reviewed Original ResearchPoor clinical outcomeB cellsBCR-ABL1Clinical outcomesPI3KAntigen-specific humoral immune responsesAntigen-specific B cell responsesAntiviral effector functionsTime of diagnosisMRNA levelsB cell responsesHumoral immune responseSurface expressionB cell populationsB-cell malignanciesB-cell receptor signalingDependent B cell activationTransplant recipient miceMalignant B-cell transformationB cell activationB cell precursorsColony formation capacityAdvisory CommitteeSrc kinaseB-cell transformation
2018
Cooperation between SYK and ZAP70 Kinases As a Driver of Oncogenic BCR-Signaling in B-Cell Malignancies
Sadras T, Cutler J, Aguade-Gorgorio J, Chen Z, Cosgun K, Pandey A, Muschen M. Cooperation between SYK and ZAP70 Kinases As a Driver of Oncogenic BCR-Signaling in B-Cell Malignancies. Blood 2018, 132: 3922. DOI: 10.1182/blood-2018-99-116954.Peer-Reviewed Original ResearchSpleen tyrosine kinaseSH2 domainZAP70 kinaseKinase domainCarboxy-terminal kinase domainLinker regionT cell receptorSurvival signalsBCR signalingTyrosine kinaseChronic lymphocytic leukemiaTandem SH2 domainsProximal signal transductionAmino acid insertB-cell malignanciesBCR-mediated signalsB cellsAlternative splice variantsNegative B cell selectionDifferential interactomeProteomic approachInterdomain BZAP70 proteinBCR componentsSignal transductionLgr5 Enables Positive B-Cell Selection and Tumor-Initiation in B-Cell Malignancies
Cosgun K, Deb G, Yang X, Xiao G, Sadras T, Auer F, Lee J, Abarientos A, Mangolini M, Aghajanirefah A, Geng H, Jumaa H, Polson A, Clevers H, Muschen M. Lgr5 Enables Positive B-Cell Selection and Tumor-Initiation in B-Cell Malignancies. Blood 2018, 132: 547. DOI: 10.1182/blood-2018-99-116956.Peer-Reviewed Original ResearchB-cell malignanciesB-cell lineageAntibody-drug conjugatesLeukemia-initiating cellsTransplant recipientsB-ALLSurface expressionCancer stem cell markersWorse overall survivalMature B cell poolPoor clinical outcomeSingle-agent treatmentΒ-cateninB cell poolB cell selectionStem cell markersΒ-catenin activationΒ-catenin target genesLGR5 overexpressionLIC frequencyOverall survivalLeukemia burdenClinical outcomesEnvironmental antigensRecipient miceCD25-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 ZenecaB-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
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