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 outcomesDynamic 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 outcomesGenetic Knockin Approaches to Reconstructing DLBCL-Subtypes from Human Germinal Center B-Cells
Khanduja D, Robinson M, Arce D, Klemm L, Leveille E, Kothari S, Caeser R, Hodson D, Müschen M. Genetic Knockin Approaches to Reconstructing DLBCL-Subtypes from Human Germinal Center B-Cells. Blood 2023, 142: 1627. DOI: 10.1182/blood-2023-190634.Peer-Reviewed Original ResearchSecondary lymphoid organsGerminal center B cellsMYD88 L265P mutationLymphoid organsLymph nodesB cellsL265P mutationHuman germinal center B cellsDLBCL subtypesNSG miceTonsillar germinal center B cellsLymphoma developmentPreclinical testingLymphoid tissue inducer cellsTransgenic expressionPoor clinical outcomeWild-type mutationsGenetic mouse modelsExon 5GC B cellsNBSGW miceClinical outcomesLTi cellsLymphoid folliclesInducer cells
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
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 inhibitorsAutonomous 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 activityDynamic 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
Lgr5 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 Zeneca
2016
Oncogenic Feedback Activation Between BCL6 and MLL Promotes Malignant Transformation in MLL-RearrangedAcute Lymphoblastic Leukemia
Hurtz C, Chan L, Ballabio E, Willman C, Carroll W, Armstrong S, Ernst P, Melnick A, Milne T, Müschen M. Oncogenic Feedback Activation Between BCL6 and MLL Promotes Malignant Transformation in MLL-RearrangedAcute Lymphoblastic Leukemia. Blood 2016, 128: 907. DOI: 10.1182/blood.v128.22.907.907.Peer-Reviewed Original ResearchFunction of Bcl6Lymphoblastic leukemiaMLL-AF4Expression levelsPhiladelphia chromosome-positive acute lymphoblastic leukemiaBCL6 levelsPharmacological inhibitionDiffuse large B-cell lymphomaLarge B-cell lymphomaChemotherapy drugs vincristineTime of diagnosisWorse clinical outcomesBCL6 expressionHigh expression levelsRelapse-free survivalAcute lymphoblastic leukemiaChronic myeloid leukemiaB-cell lymphomaHigh-risk regimenMLL-ENLTransplant recipient miceB cell precursorsReporter mouse modelWestern blot analysisClinical outcomesFeedback Regulation of STAT5 Is Critical to Balance MYC and BCL6-Dependent Transcriptional Programs That Regulate Cell Size and Glucose Metabolism
Chen Z, Geng H, Klemm L, Chan L, Daniel B, Alexander W, Willman C, Müschen M. Feedback Regulation of STAT5 Is Critical to Balance MYC and BCL6-Dependent Transcriptional Programs That Regulate Cell Size and Glucose Metabolism. Blood 2016, 128: 4069. DOI: 10.1182/blood.v128.22.4069.4069.Peer-Reviewed Original ResearchBCR-ABL1Survival rateMedian expressionAdult B-lineageFree survival rateOverall survival rateWorse clinical outcomesGroup of patientsHigh expression levelsLeukemia cellsMRNA levelsNOD-SCID miceMYC expressionTyrosine kinase inhibitorsBCR-ABL1 tyrosine kinaseExpression levelsKinase inhibitory regionMedical Research CouncilAdvisory CommitteeInhibition of mTORGlucose consumptionCOG trialsLeukemia regressionTyrosine kinaseClinical outcomesCD25 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 outcome
2014
IL2RA (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 development
2013
Identification Of FOXM1 As Therapeutic Target In BCR-ABL1 Positive Acute Lymphoblastic Leukemia
Buchner M, Park E, Klemm L, Geng H, Kopanja D, Raychaudhuri P, Muschen M. Identification Of FOXM1 As Therapeutic Target In BCR-ABL1 Positive Acute Lymphoblastic Leukemia. Blood 2013, 122: 1250. DOI: 10.1182/blood.v122.21.1250.1250.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsAcute lymphoblastic leukemiaPositive acute lymphoblastic leukemiaPoor clinical outcomeFoxM1 expression levelBCR-ABL1Clinical outcomesB cell precursorsImatinib treatmentLymphoblastic leukemiaDisease progressionBreakpoint cluster regionTherapeutic targetBCR-ABL1 tyrosine kinase activityCatalase expressionPhiladelphia chromosome-positive acute lymphoblastic leukemiaSmall molecule tyrosine kinase inhibitorsFoxm1 deletionExpression levelsMolecule tyrosine kinase inhibitorsCell precursorsDeletion of Foxm1Münster Study GroupGood clinical responseIntracellular reactive oxygen species (ROS) formationIdentification Of BCL6 As a Therapeutic Target In MLL-Rearranged ALL
Hurtz C, Geng H, Ballabio E, Xiao G, Ng C, Masouleh B, Willman C, Armstrong S, Milne T, Melnick A, Muschen M. Identification Of BCL6 As a Therapeutic Target In MLL-Rearranged ALL. Blood 2013, 122: 72. DOI: 10.1182/blood.v122.21.72.72.Peer-Reviewed Original ResearchDiffuse large B-cell lymphomaFunction of Bcl6White blood countPoor clinical outcomeAcute lymphoblastic leukemiaMinimal residual diseaseClinical outcomesMLL-AF4Clinical trialsBCL6 levelsPositive minimal residual diseasePharmacological inhibitionHigher white blood countExpression levelsLarge B-cell lymphomaAberrant expressionChemotherapy drugs vincristineBCL6 protein levelsTime of diagnosisWorse clinical outcomesBCL6 expressionRelapse-free survivalProtein levelsPediatric clinical trialsB-cell lymphomaTargeting Pre-B Cell Receptor and BCL6 In TCF3-PBX1 B-Lineage Acute Lymphoblastic Leukemia
Geng H, Hurtz C, Chen Z, Chen W, Ballabio E, Xiao G, Kweon S, Nahar R, Sojaee S, Chan L, Masouleh B, Sykes D, Melnick A, Roeder R, Milne T, Muschen M. Targeting Pre-B Cell Receptor and BCL6 In TCF3-PBX1 B-Lineage Acute Lymphoblastic Leukemia. Blood 2013, 122: 349. DOI: 10.1182/blood.v122.21.349.349.Peer-Reviewed Original ResearchPre-BCR signalingGene expression microarray dataB-lineage acute lymphoblastic leukemiaExpression microarray dataTyrosine kinase inhibitorsPre-B cell receptorCell deathMicroarray dataPre-BCR componentsPoor clinical outcomeAcute lymphoblastic leukemiaTCF3-PBX1Cell line 697Cell cycle arrestTranscriptional repressor BCL6ChIPseq dataPre-BCRChIP-seqCellular processesClinical outcomesCritical survival factorTherapeutic targetLeukemia cellsLymphoblastic leukemiaTransplant recipient mice
2012
Integrative Analysis of Ikaros-Dependent Changes of Transcriptional Regulation and Tyrosine Phosphorylation Events in Ph+ ALL
Geng H, Nahar R, Ramezani-Rad P, Chen Z, Tyner J, Chang B, Titz B, Buchner M, Hurtz C, Graeber T, Druker B, Paietta E, Melnick A, Willman C, Carroll W, Muschen M. Integrative Analysis of Ikaros-Dependent Changes of Transcriptional Regulation and Tyrosine Phosphorylation Events in Ph+ ALL. Blood 2012, 120: 528. DOI: 10.1182/blood.v120.21.528.528.Peer-Reviewed Original ResearchGene expression changesTyrosine phosphorylation eventsExpression changesTarget genesPhosphorylation eventsIkaros functionTyrosine phosphorylationClinical trial fundingTumor suppressorAbility of IkarosDependent survival signalsTyrosine kinase LckClinical trialsSet of genesBCL6 target genesComprehensive gene expression analysisChIP-seq dataIkaros transcription factorGene expression analysisRole of IkarosGene expression microarraysTrial fundingBristol-Myers SquibbClinical outcomesFurther biochemistrySOX4 enables Oncogenic Survival Signals in Acute Lymphoblastic Leukemia
Ramezani-Rad P, Geng H, Chan L, Hurtz C, Jumaa H, Melnick A, Paietta E, Carroll W, Willman C, Lefebvre V, Muschen M. SOX4 enables Oncogenic Survival Signals in Acute Lymphoblastic Leukemia. Blood 2012, 120: 863. DOI: 10.1182/blood.v120.21.863.863.Peer-Reviewed Original ResearchARF/p53PI3K/AktTranscription factorsPoor clinical outcomeNegative regulationBCR-ABL1B cell precursorsPre-B cell transitionClinical outcomesDe-phosphorylation eventsCpG methylation analysisMRNA levelsPre-B cell receptor checkpointMyeloid leukemiaP110 catalytic subunitCytokine receptor signalingB cell developmentB-cell lineage leukemiaSOX4 transcription factorTyrosine kinase inhibitor treatmentPI3K/Akt pathwayCell precursorsT cell developmentCritical upstream regulatorPutative DNA