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 inhibitorsMYC to BCL6 State-Transitions Determine Cell Size and Metabolic Fluctuations and Define a Novel Biorhythm in B-Cell Malignancies
Cheng Z, Kume K, Müschen M. MYC to BCL6 State-Transitions Determine Cell Size and Metabolic Fluctuations and Define a Novel Biorhythm in B-Cell Malignancies. Blood 2023, 142: 2769. DOI: 10.1182/blood-2023-190972.Peer-Reviewed Original ResearchGerminal center-derived B-cell lymphomaB cell developmentCell size fluctuationsCell cycleImmunoglobulin light chain gene recombinationDNA damage-induced apoptosisDistinct cellular statesNormal B cell developmentDamage-induced apoptosisExit cell cycleCell sizeB cell transitionGene expression profilesQuiescent phenotypeOncogenic tyrosine kinasesCell cycle arrestActivation of autophagySingle-cell sortingCellular statesCell divisionHigher glycolysis activityMYC transcriptionB cell cycleSuppression of glycolysisExpression profiles
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 BCL6PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis
Pan L, Hong C, Chan LN, Xiao G, Malvi P, Robinson ME, Geng H, Reddy ST, Lee J, Khairnar V, Cosgun KN, Xu L, Kume K, Sadras T, Wang S, Wajapeyee N, Müschen M. PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2016553118. PMID: 33531346, PMCID: PMC7896313, DOI: 10.1073/pnas.2016553118.Peer-Reviewed Original ResearchConceptsTransplant recipient miceDNA double-strand breaksNormal B cell developmentDouble-strand breaksB cell developmentGenetic deletionB cellsLymphoid transcription factorsGlucose transporter GLUT1Gatekeeper functionGlucose uptakeRecipient miceTranscription factorsSomatic recombinationSynthetic lethalityB-cell acute lymphoblastic leukemiaCell developmentMetabolic gatekeeperRefractory B-ALLDeficient murineCell acute lymphoblastic leukemiaPoor clinical outcomeCell typesAcute lymphoblastic leukemiaGlucose transport
2019
Rationale for Targeting BCL6 in MLL-Rearranged B-ALL
Chan L, Hurtz C, Geng H, Ballabio E, Xiao G, Deb G, Khoury H, Armstrong S, Ernst P, Melnick A, Milne T, Müschen M. Rationale for Targeting BCL6 in MLL-Rearranged B-ALL. Blood 2019, 134: 1239. DOI: 10.1182/blood-2019-131565.Peer-Reviewed Original ResearchB-cell acute lymphoblastic leukemiaPharmacological inhibitionABT-199Group of patientsBCL6 expressionBone marrow biopsyPoor clinical outcomeAcute lymphoblastic leukemiaBCL2 inhibitor ABT-199BH3 mimetic ABT-199MLL gene rearrangementTransplant recipient miceMLL fusionsB-cell transformationClinical outcomesMarrow biopsyTreatment of MLLDismal outcomeLymphoblastic leukemiaRecipient miceNormal B cell developmentSelective vulnerabilityImmunohistochemical stainingInfant BSmall molecule inhibitorsSignaling 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 modelsRationale for targeting BCL6 in MLL-rearranged acute lymphoblastic leukemia
Hurtz C, Chan LN, Geng H, Ballabio E, Xiao G, Deb G, Khoury H, Chen CW, Armstrong SA, Chen J, Ernst P, Melnick A, Milne T, Müschen M. Rationale for targeting BCL6 in MLL-rearranged acute lymphoblastic leukemia. Genes & Development 2019, 33: 1265-1279. PMID: 31395741, PMCID: PMC6719625, DOI: 10.1101/gad.327593.119.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiomarkers, TumorCell SurvivalCells, CulturedGene DeletionGene Expression Regulation, LeukemicGene TargetingHumansMiceMyeloid-Lymphoid Leukemia ProteinOncogene Proteins, FusionPrecursor Cell Lymphoblastic Leukemia-LymphomaPrognosisPromoter Regions, GeneticProto-Oncogene Proteins c-bcl-6ConceptsB-cell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaLymphoblastic leukemiaPharmacological inhibitionGroup of patientsBCL6 expressionBone marrow biopsyBH3 mimetic ABT-199Transplant recipient miceMLL fusionsB-cell transformationMarrow biopsyTreatment of MLLDismal outcomeRecipient miceNormal B cell developmentImmunohistochemical stainingTranscriptional activationB cell developmentMalignant transformationDrug resistanceGenetic deletionPatient samplesExpression of BimMLL-ENL fusion
2018
Divergent Evolutionary Trajectories of Erk- and Stat5-Activating Lesions in Acute Lymphoblastic Leukemia
Chan L, Shojaee S, Hurtz C, Auer F, Chen Z, Cosgun K, Geng H, Sadras T, White D, Muschen M. Divergent Evolutionary Trajectories of Erk- and Stat5-Activating Lesions in Acute Lymphoblastic Leukemia. Blood 2018, 132: 568. DOI: 10.1182/blood-2018-99-115536.Peer-Reviewed Original ResearchEvolutionary trajectoriesColony formation abilityCompetitive fitnessCommitment stepPre-B cell receptorDivergent evolutionary trajectoriesUpstream kinase MEKNormal B cell developmentOncogenic signal transductionInducible ablationActivation of STAT5B cell developmentEmpty vector controlActivation of ERKCentral oncogenic driverB-cell transformationImmature B cellsSignal transductionFormation abilityKinase MEKPhosphorylation of ERKGrowth factor receptorPatient-derived preAlternative pathwayERK activityCD25-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 Zeneca
2015
Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia
Buchner M, Park E, Geng H, Klemm L, Flach J, Passegué E, Schjerven H, Melnick A, Paietta E, Kopanja D, Raychaudhuri P, Müschen M. Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia. Nature Communications 2015, 6: 6471. PMID: 25753524, PMCID: PMC4366523, DOI: 10.1038/ncomms7471.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsAntineoplastic AgentsB-LymphocytesCell ProliferationCell SurvivalChildClinical Trials as TopicCyclin-Dependent Kinase Inhibitor p16Drug Resistance, NeoplasmForkhead Box Protein M1Forkhead Box Protein O3Forkhead Transcription FactorsGene Expression Regulation, LeukemicHumansMicePeptidesPrecursor Cell Lymphoblastic Leukemia-LymphomaSignal TransductionSurvival AnalysisThiostreptonXenograft Model Antitumor AssaysConceptsAcute lymphoblastic leukemiaLymphoblastic leukemiaTherapeutic targetB-cell lineage acute lymphoblastic leukemiaFOXM1 levelsAggressive clinical coursePre-B cell receptor checkpointNovel therapeutic targetB cell populationsNormal B cell populationsClinical coursePoor outcomeCure rateNormal B cell developmentFOXM1 inhibitionB cell developmentDrug resistanceFoxm1 deletionFOXM1Colony formationPatientsLeukemiaCell survivalPrognosisTranscriptional inactivation
2014
Divergent Lineage-Specific Functions of PP2A in Chronic Phase CML and Lymphoid Blast Crisis
Xiao G, Geng H, Chan L, Chen Z, Muschen M. Divergent Lineage-Specific Functions of PP2A in Chronic Phase CML and Lymphoid Blast Crisis. Blood 2014, 124: 3128. DOI: 10.1182/blood.v124.21.3128.3128.Peer-Reviewed Original ResearchFunction of PP2ACell lineagesB cell developmentB-cell lineageSer/Thr phosphataseCell developmentPI3K-AktEarly B cell developmentProtein phosphatase 2ALineage-specific functionsNormal B cell developmentChronic phase chronic myeloid leukemiaLineage-specific requirementGlycolytic fluxPre-B cell receptor checkpointMyeloid lineagePhase chronic myeloid leukemiaChronic myeloid leukemiaRegulation of AktS6 ribosomal proteinHigh glycolytic fluxRapid cell deathLymphoid blast crisisImportant tumor suppressorColony formation capabilityIL2RA (CD25) Recruits Inhibitory Phosphatases to the Cell Membrane and Mediates Negative Feedback Control of STAT5 Signaling in Acute Lymphoblastic Leukemia
Geng H, Lee J, Chen Z, Masouleh B, Hurtz C, Park E, Xiao G, Parekh S, Kornblau S, Melnick A, Paietta E, Muschen M. IL2RA (CD25) Recruits Inhibitory Phosphatases to the Cell Membrane and Mediates Negative Feedback Control of STAT5 Signaling in Acute Lymphoblastic Leukemia. Blood 2014, 124: 788. DOI: 10.1182/blood.v124.21.788.788.Peer-Reviewed Original ResearchCD25 expressionB cell developmentClinical outcomesPoor overall clinical outcomeHuman prePatient-derived preHigh-risk subsetNegative feedback controlTime of diagnosisOverall clinical outcomePoor clinical outcomeHigh-risk subtypesLeukemia initiationAcute lymphoblastic leukemiaCell developmentPhosphorylation levelsImmune precipitationColony formation capacityTransplant recipientsTyrosine kinaseTransplant settingLymphoblastic leukemiaIL-2Cell surface expressionNormal B cell developmentFOXM1 Mediates Drug-Resistance and Represents a Therapeutic Target in Pre-B Acute Lymphoblastic Leukemia
Buchner M, Park E, Klemm L, Geng H, Kopanja D, Raychaudhuri P, Muschen M. FOXM1 Mediates Drug-Resistance and Represents a Therapeutic Target in Pre-B Acute Lymphoblastic Leukemia. Blood 2014, 124: 790. DOI: 10.1182/blood.v124.21.790.790.Peer-Reviewed Original ResearchB cell developmentFOXM1 protein levelsAcute lymphoblastic leukemiaB cell progenitorsB cell precursorsCell developmentFOXO factorsRegulation of FoxM1BCR-ABL1Cell lineagesB-cell lineageBox transcription factor familyCell progenitorsProtein levelsEarly B cell developmentLymphoblastic leukemiaTranscription factor familyCell precursorsGene expression surveyFoxM1 downregulationNormal B cell developmentPre-B cell receptor checkpointFOXM1 expressionTherapeutic targetB cellsThe Linker Protein GAS7 Negatively Regulates Pre-B Cell Differentiation and Amplifies Proliferation and Survival Signals in Acute Lymphoblastic Leukemia
Lee J, Buchner M, Geng H, Swaminathan S, Park E, Park A, Lin-Chao S, So C, Muschen M. The Linker Protein GAS7 Negatively Regulates Pre-B Cell Differentiation and Amplifies Proliferation and Survival Signals in Acute Lymphoblastic Leukemia. Blood 2014, 124: 3777. DOI: 10.1182/blood.v124.21.3777.3777.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaTyrosine kinase inhibitorsLymphoblastic leukemiaBCR-ABL1B-cell lineage leukemiaPre-B cell differentiationTyrosine kinase inhibitor treatmentPediatric acute lymphoblastic leukemiaTreatment-related acute myeloid leukemiaAcute myeloid leukemiaPre-B cell receptor checkpointKinase inhibitor treatmentEffects of Stat5Spontaneous IgNormal B cell developmentMyeloid leukemiaB cell progenitorsBone marrowCell differentiationInhibitor treatmentB cell developmentLeukemiaSelf-renewal capacityConditional deletionKinase inhibitors
2009
BCL6 Is Critical for the Development of a Diverse Primary B Cell Repertoire.
Duy C, Yu J, Swaminathan S, Nahar R, Kweon S, Polo J, Valls E, Klemm L, Cerchietti L, von Levetzow G, Herzog S, Jumaa H, de Alborán I, Melnick A, Ye B, Müschen M. BCL6 Is Critical for the Development of a Diverse Primary B Cell Repertoire. Blood 2009, 114: 91. DOI: 10.1182/blood.v114.22.91.91.Peer-Reviewed Original ResearchB cell developmentDNA damage stressTranscriptional repressionCell developmentPrimary B-cell repertoireBCL6 functionB cell precursorsDNA damage-induced apoptosisDNA damage response pathwayActive STAT5 mutantDNA damageEarly B cell developmentB cell repertoireNormal B cell developmentDamage response pathwayDamage-induced apoptosisEarly B cell differentiationGene expression patternsCell precursorsPre-B cell populationsSelf-renewal defectGene expression analysisDamage stressSimilar expression levelsEarly B-cell precursors