2023
STAT5-Feedback Controls Distinct Metabolic States for Dynamic Transitions between Cellular Activation and Quiescence in Acute Lymphoblastic Leukemia
Kume K, Chen Z, Robinson M, Chan L, Leveille E, Cosgun K, Cheng Z, Arce D, Khanduja D, Graeber T, Müschen M. STAT5-Feedback Controls Distinct Metabolic States for Dynamic Transitions between Cellular Activation and Quiescence in Acute Lymphoblastic Leukemia. Blood 2023, 142: 2977. DOI: 10.1182/blood-2023-191006.Peer-Reviewed Original ResearchB-cell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaLymphoblastic leukemiaPharmacological inhibitionGenetic deletionCellular activationReceptor signalingCell deathBone marrow relapsePoor overall outcomePoor clinical outcomeLeukemia-initiating capacityOncogenic STAT5Mass spectrometry-based metabolomics analysisExpression levelsPhosphorylation of STAT5Flow cytometry analysisMetabolic statePositive MRDRole of mTORMarrow relapseAggressive courseClinical outcomesExcessive protein synthesisMetabolic outcomesImmunoglobulin 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-LCRepurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies
Cosgun K, Robinson M, Oulghazi S, Xu L, Xiao G, Chan L, Lee J, Kume K, Leveille E, Arce D, Khanduja D, Feldhahn N, Song J, Chan W, Chen J, Taketo M, Schjerven H, Jellusova J, Kothari S, Davids M, Müschen M. Repurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies. Blood 2023, 142: 2818. DOI: 10.1182/blood-2023-190522.Peer-Reviewed Original ResearchFavorable safety profileSmall molecule inhibitorsT-lymphoid malignancyΒ-catenin degradationLymphoid malignanciesΒ-cateninInteractome studiesSafety profileClinical trialsMolecule inhibitorsLow nanomolar concentrationsΒ-catenin accumulationSolid tumorsRefractory B-cell malignanciesCell deathPK/PD profilesZinc finger proteinRefractory lymphoid malignanciesChIP-seq analysisPhase 2 trialMYC target genesT-cell lymphomaColony formationRapid nuclear accumulationWnt/β-catenin pathwayDynamic 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 outcomesNegative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression
Ecker V, Brandmeier L, Stumpf M, Giansanti P, Moreira A, Pfeuffer L, Fens M, Lu J, Kuster B, Engleitner T, Heidegger S, Rad R, Ringshausen I, Zenz T, Wendtner C, Müschen M, Jellusova J, Ruland J, Buchner M. Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression. Cell Reports 2023, 42: 113017. PMID: 37792532, DOI: 10.1016/j.celrep.2023.113017.Peer-Reviewed Original ResearchConceptsMitogen-activated protein kinaseChronic lymphocytic leukemiaCLL cellsMitochondrial reactive oxygen speciesChronic lymphocytic leukemia progressionApoptotic cell deathPoor clinical prognosisCLL cell survivalSmall molecule inhibitorsNegative feedback regulationProtein kinaseReactive oxygen speciesMAPK signalingMAPK activityPromising treatment conceptClinical prognosisClinical challengeLymphocytic leukemiaCell survivalAcute activationCell deathDNA damageDUSP6Treatment conceptFeedback regulationβ-catenin engages IKZF factors to control lymphopoiesis
Cosgun K, Jumaa H, Robinson M, Xu L, Xiao G, Arce D, Khanduja D, Chan L, Lee J, Schjerven H, Jellusova J, Müschen M. β-catenin engages IKZF factors to control lymphopoiesis. The Journal Of Immunology 2023, 210: 65.09-65.09. DOI: 10.4049/jimmunol.210.supp.65.09.Peer-Reviewed Original ResearchΒ-cateninZinc finger transcription factorFinger transcription factorDramatic nuclear accumulationGSK3β-dependent phosphorylationT cell signalingT cell developmentTCF factorsRepressive complexesTranscriptional controlEnhancer clusterInteractome studiesTranscriptional activationΒ-catenin activationCommon oncogenic driversInhibition of GSK3βTranscription factorsNegative regulationMesenchymal lineagesNuclear accumulationCell deathMYCT-lymphoid malignancyΒ-catenin expressionPromotes Proliferation
2021
Identification of BCL6 As Synthetic Lethality in RAS-Driven B-Cell Transformation
Chan L, Hurtz C, Leveille E, Kume K, Robinson M, Geng H, Cosgun K, Müschen M. Identification of BCL6 As Synthetic Lethality in RAS-Driven B-Cell Transformation. Blood 2021, 138: 792. DOI: 10.1182/blood-2021-148653.Peer-Reviewed Original ResearchRAS-ERK pathwayB cell developmentNormal B cell developmentRAS-ERKCell deathTransplant recipient miceSynthetic lethalityGenetic lesionsBCL6 expressionGenetic ablationChIP-seq analysisRAS-ERK signalingPermanent activationMurine B cell precursorsB cell precursorsDeletion of Bcl6Pharmacological inhibitionDoxycycline-inducible expressionSmall molecule inhibitionNegative B cell selectionSmall molecule inhibitorsExpression of PRDM1BCL6 promoterB-cell transformationExpression of BCL6
2019
Targeting Unique Synthetic Lethal Interactions between PI3K and MYC in B-ALL
Xiao G, Kume K, Geng H, Han T, Klemm L, Müschen M. Targeting Unique Synthetic Lethal Interactions between PI3K and MYC in B-ALL. Blood 2019, 134: 3785. DOI: 10.1182/blood-2019-128719.Peer-Reviewed Original ResearchMYC protein levelsPI3KCell deathMYC overexpressionPTEN deletionRescue effectProtein levelsPI3K hyperactivationMYC protein stabilityTranscription factor Pax5Wild-type MycDegradation of MycSynthetic lethal interactionsGlutamine consumptionGene expression profilesCellular ATP levelsInhibition of glutaminolysisATP levelsPTEN inhibitor SF1670Deletion of PTENMyc mutantsPI3K pathwayPI3K subunitsMyc proteinProtein geneCo-Expression of SYK and ZAP70 Subverts Negative B-Cell Selection and Enables Oncogenic Signaling in Multiple B-Cell Malignancies
Sadras T, Martin M, Kim-Sing L, Cutler J, Lenz G, Knapp A, Ghergus D, Delmotte F, Schleiss C, Korganow A, Soulas-Sprauel P, Chen Z, Pandey A, Weinstock D, Jumaa H, Meffre E, Martin T, Müschen M. Co-Expression of SYK and ZAP70 Subverts Negative B-Cell Selection and Enables Oncogenic Signaling in Multiple B-Cell Malignancies. Blood 2019, 134: 295. DOI: 10.1182/blood-2019-128999.Peer-Reviewed Original ResearchB-cell chronic lymphocytic leukemiaNegative B cell selectionB cellsB-cell malignanciesB cell selectionCo-expressing cellsT cellsBCR-stimulated B cellsZAP70 expressionMultiple B-cell malignanciesLymphoma cellsAutoreactive BCRsCentral tolerance checkpointsCell deathT cell populationsB cell compartmentChronic lymphocytic leukemiaProximity ligation assayB-cell lymphoma cellsMantle cell lymphomaTumor B cellsExpression of ZAP70Human B-cell lymphoma cellsImmature B cellsDevelopment of leukemiaMetabolic 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
Autoimmunity Checkpoints As Therapeutic Targets in B-Cell Malignancies
Chen Z, Muschen M. Autoimmunity Checkpoints As Therapeutic Targets in B-Cell Malignancies. Blood 2018, 132: 1587. DOI: 10.1182/blood-2018-99-113674.Peer-Reviewed Original ResearchAutoreactive B-cell antigen receptorsB-cell malignanciesAcute lymphoblastic leukemiaAutoreactive B cellsB cellsCell malignanciesB cell antigen receptorNormal B cellsTypes of cancerAIC activationTargeted therapyAutoreactive clonesMalignant transformationTargeted activationAutoreactive B lymphocytesLymphocyte developmentPI3KB-cell lymphomaB-lymphoid malignanciesB-cell receptor signalingDrug-resistant leukemiaB-cell leukemiaB-cell tumorsCell deathNegative selectionDUSP1/6 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 cellsSHIP1 Inhibition As Novel Therapeutic Approach in Chronic Lymphocytic Leukemia
Ecker V, Braun M, Neumayer T, Muschen M, Ruland J, Buchner M. SHIP1 Inhibition As Novel Therapeutic Approach in Chronic Lymphocytic Leukemia. Blood 2018, 132: 894. DOI: 10.1182/blood-2018-99-117053.Peer-Reviewed Original ResearchChronic lymphocytic leukemiaMyeloid-derived suppressor cellsSecondary lymphoid organsImmune cell functionPeripheral bloodCLL cellsLymph nodesMalignant CLL cellsB cellsT cellsImmune responseLymphoid organsLymphocytic leukemiaSmall molecule inhibitorsSHIP1 inhibitionAge-matched healthy donorsAnti-tumor immune responsePharmacological inhibitionCell deathCLL peripheral bloodTreatment-related toxicityImmunoglobulin-producing plasma cellsRegulatory T cellsCell functionCLL cell deathAutonomous Ca2+ Oscillations Reflect Oncogenic BCR-Signaling in Multiple B-Cell Malignancies and Are Essential for Survival and Proliferation
Kume K, Chen L, Lee J, Muschen M. Autonomous Ca2+ Oscillations Reflect Oncogenic BCR-Signaling in Multiple B-Cell Malignancies and Are Essential for Survival and Proliferation. Blood 2018, 132: 1373. DOI: 10.1182/blood-2018-99-117315.Peer-Reviewed Original ResearchAutonomous Ca2B-cell malignanciesBCR signalingProliferation signalsTime of diagnosisExpression levelsINCA-6B-ALLCell deathMantle cell lymphomaMedian expression levelBCR-ABL1Store-operated Ca2Cell lymphomaHigh expression levelsGenetic experimentsT-cell factorMyeloma cellsPatient-derived xenograft modelsMultiple B-cell malignanciesSurvival signalsFunctional BCRSTIM1/2Relapse-free survivalB-cell lymphoma cells
2016
Identification of the Energy Stress Sensor AMPK As Therapeutic Target in Acute Lymphoblastic Leukemia
Chan L, Lee J, Cosgun K, Geng H, Xiao G, Chen Z, Ernst T, Hochhaus A, Müschen M. Identification of the Energy Stress Sensor AMPK As Therapeutic Target in Acute Lymphoblastic Leukemia. Blood 2016, 128: 2771. DOI: 10.1182/blood.v128.22.2771.2771.Peer-Reviewed Original ResearchChronic myeloid leukemiaAcute lymphoblastic leukemiaMyeloid leukemiaTransplant recipient miceB-cell lineageLKB1/AMPKLymphoblastic leukemiaRecipient miceCML cellsTherapeutic targetLong-term disease-free survivalPhiladelphia chromosome-positive acute lymphoblastic leukemiaB-cell lineage leukemiaPatient-derived preDisease-free survivalInducible deletionNovel therapeutic targetGlycolytic activityBCR-ABL1 tyrosine kinaseNovel therapeutic avenuesATP levelsMitochondrial functionCell deathInitial remissionClinical characteristicsPTEN 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
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 outcomeB-Lymphoid Transcription Factors Restrict Glycolytic Energy Supply for Oncogenic Signaling
Chan L, Chen Z, Braas D, Geng H, Hurtz C, Shojaee S, Cazzaniga V, Ng C, Ernst T, Hochhaus A, Kornblau S, Cazzaniga G, Liu G, Milne T, Koeffler H, Armstrong S, Dickins R, Yamamoto K, Graeber T, Muschen M. B-Lymphoid Transcription Factors Restrict Glycolytic Energy Supply for Oncogenic Signaling. Blood 2015, 126: 1255. DOI: 10.1182/blood.v126.23.1255.1255.Peer-Reviewed Original ResearchGlycolytic energy supplyLKB1-AMPKB cellsTranscription factorsGlucose uptakeMyeloid leukemiaMyeloid malignanciesDeletion of Lkb1Unknown functional significanceB-lineage leukemiasTranscriptional repressionTranscriptional programsMyeloid leukemia cellsLineage conversionHematopoietic progenitor cellsOncogenic signalingClinical characteristicsLineage shiftGenetic lesionsCell deathGlycolytic reserveOncogenic lesionsLeukemia casesInsulin receptorGlucocorticoid receptorPP2A Is Required for B Cell Survival and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia
Gang X, Geng H, Chan L, Chen Z, Jiang X, Muschen M. PP2A Is Required for B Cell Survival and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia. Blood 2015, 126: 902. DOI: 10.1182/blood.v126.23.902.902.Peer-Reviewed Original ResearchLB-100B cell survivalCell deathH2AX phosphorylationSer/Thr protein phosphatase 2ACell lineagesCell-specific vulnerabilityCell survivalFunction of PP2AEarly B cell developmentProtein phosphatase 2AB-cell lineageCatalytic subunit CGlycolytic fluxAnti-oxidant gene expressionTumor suppressor functionRapid cell deathS6 ribosomal proteinHigh glycolytic fluxB cell developmentImportant tumor suppressorPro-survival roleHigher reactive oxygen species (ROS) levelsCre-mediated deletionPP2A subunitsErk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia
Shojaee S, Caeser R, Buchner M, Park E, Swaminathan S, Hurtz C, Geng H, Chan LN, Klemm L, Hofmann WK, Qiu YH, Zhang N, Coombes KR, Paietta E, Molkentin J, Koeffler HP, Willman CL, Hunger SP, Melnick A, Kornblau SM, Müschen M. Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia. Cancer Cell 2015, 28: 114-128. PMID: 26073130, PMCID: PMC4565502, DOI: 10.1016/j.ccell.2015.05.008.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Transformation, NeoplasticDNA-Binding ProteinsDual Specificity Phosphatase 6Host Cell Factor C1HumansIntracellular Signaling Peptides and ProteinsMAP Kinase Signaling SystemMembrane ProteinsMiceMice, TransgenicMolecular Sequence DataPrecursor Cell Lymphoblastic Leukemia-LymphomaPrognosisProtein Serine-Threonine KinasesSmall Molecule LibrariesTranscription FactorsConceptsAcute lymphoblastic leukemiaLymphoblastic leukemiaPatient-derived preNegative feedback regulationPre-B cell cloneCell deathImmediate cell deathMouse modelSmall molecule inhibitorsTherapeutic targetAcute activationMalignant transformationCell clonesFeedback regulationOncogenic signalingMolecule inhibitorsStrong activationLeukemiaDeathERKPre-B-cell transformationCell transformationActivationOncogenic transformationVast majority