2023
The Transcriptional Landscape of Ph+B-ALL Is Orchestrated By Long-Range Enhancer-Promoter Interactions and the Coordinated Action of Phosphorylation-Dependent and Phosphorylation-Independent Transcription Factors
Ng H, Robinson M, Malysheva V, Deniz O, Crump N, Cosgun K, Helian K, Spivakov M, Müschen M, Feldhahn N. The Transcriptional Landscape of Ph+B-ALL Is Orchestrated By Long-Range Enhancer-Promoter Interactions and the Coordinated Action of Phosphorylation-Dependent and Phosphorylation-Independent Transcription Factors. Blood 2023, 142: 2779. DOI: 10.1182/blood-2023-173435.Peer-Reviewed Original ResearchTranscription factorsTranscriptional programsEnhancer signatureGene expressionChromatin interactionsTranscriptional changesTyrosine kinaseAdditional transcription factorsMotif enrichment analysisPromoter-enhancer interactionsCis-regulatory elementsEnhancer-promoter interactionsPromoter capture HiNon-promoter regionsUnique transcriptional programGene expression changesCoordinated actionMurine B cell precursorsOncogenic tyrosine kinasesEnhancer usageActive chromatinActive genesEnhancer landscapeTranscriptional landscapeActive enhancers
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 transductionIFITM3-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 topology
2016
Feedback 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 outcomesPre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition
Köhrer S, Havranek O, Seyfried F, Hurtz C, Coffey G, Kim E, ten Hacken E, Jäger U, Vanura K, O'Brien S, Thomas D, Kantarjian H, Ghosh D, Wang Z, Zhang M, Ma W, Jumaa H, Debatin K, Müschen M, Meyer L, Davis R, Burger J. Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition. Leukemia 2016, 30: 1246-1254. PMID: 26847027, PMCID: PMC5459356, DOI: 10.1038/leu.2016.9.Peer-Reviewed Original ResearchConceptsB-cell acute lymphoblastic leukemiaSpleen tyrosine kinaseAcute lymphoblastic leukemiaPI3K/AktLymphoblastic leukemiaTherapeutic targetPrecursor B-cell acute lymphoblastic leukemiaPromising new therapeutic targetNew therapeutic targetsGene expression signaturesImmune phenotypeImportant downstream mediatorSYK inhibitionMouse modelPre-BCR signalingReceptor signalingDownstream mediatorExpression signaturesGenetic disruptionLeukemiaExquisite dependencyTyrosine kinaseAktFOXO1Signaling
2015
CD25 (IL2RA) Orchestrates Negative Feedback Control and Stabilizes Oncogenic Signaling Strength in Acute Lymphoblastic Leukemia
Lee J, Chen Z, Geng H, Xiao G, Eugene P, Parekh S, Kornblau S, Melnick A, Abbas A, Paietta E, Muschen M. CD25 (IL2RA) Orchestrates Negative Feedback Control and Stabilizes Oncogenic Signaling Strength in Acute Lymphoblastic Leukemia. Blood 2015, 126: 1434. DOI: 10.1182/blood.v126.23.1434.1434.Peer-Reviewed Original ResearchPre-BCR signalingPre-B cell receptorCytoplasmic tailOncogenic tyrosine kinasesB cell developmentTyrosine kinaseSerine/threonine protein kinaseCell developmentConstitutive membrane localizationCytoplasmic interaction partnersReceptor chainsEarly B cell developmentThreonine protein kinaseDownstream tyrosine kinasePre-B cell stageShort cytoplasmic tailNegative feedback controlComprehensive gene expression analysisDependent signal transductionTyrosine kinase BtkTyrosine kinase oncogenesGene expression analysisSerial transplantation experimentsB lineage cellsAbsence of CD25Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia
Geng H, Hurtz C, Lenz KB, Chen Z, Baumjohann D, Thompson S, Goloviznina NA, Chen WY, Huan J, LaTocha D, Ballabio E, Xiao G, Lee JW, Deucher A, Qi Z, Park E, Huang C, Nahar R, Kweon SM, Shojaee S, Chan LN, Yu J, Kornblau SM, Bijl JJ, Ye BH, Ansel KM, Paietta E, Melnick A, Hunger SP, Kurre P, Tyner JW, Loh ML, Roeder RG, Druker BJ, Burger JA, Milne TA, Chang BH, Müschen M. Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia. Cancer Cell 2015, 27: 409-425. PMID: 25759025, PMCID: PMC4618684, DOI: 10.1016/j.ccell.2015.02.003.Peer-Reviewed Original ResearchMeSH KeywordsBasic Helix-Loop-Helix Transcription FactorsClinical Trials as TopicDNA-Binding ProteinsGene Expression Regulation, NeoplasticHumansIntracellular Signaling Peptides and ProteinsMolecular Sequence DataPhosphatidylinositol 3-KinasePre-B-Cell Leukemia Transcription Factor 1Precursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidProtein-Tyrosine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-6Signal TransductionSrc-Family KinasesSyk KinaseUp-RegulationConceptsDistinct subtypesPre-BCR signalingPatient-derived preVivo treatment studiesTreatment of patientsAcute lymphoblastic leukemiaTyrosine kinase inhibitorsPre-B cell receptor signalingCell receptor signalingLymphoblastic leukemiaClinical trialsTreatment studiesPre-BCR functionReceptor signalingKinase inhibitorsDistinct subsetsBCL6 expressionInduced activationFeedback activationSubtypesTyrosine kinaseBCL6SignalingActivationTranscriptional level
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
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 kinase
2011
Compensatory Signaling From ROR1 and the Pre-B Cell Receptor Promote Survival of t(1;19) Acute Lymphoblastic Leukemia
Bicocca V, Chang B, Muschen M, Druker B, Tyner J. Compensatory Signaling From ROR1 and the Pre-B Cell Receptor Promote Survival of t(1;19) Acute Lymphoblastic Leukemia. Blood 2011, 118: 2466. DOI: 10.1182/blood.v118.21.2466.2466.Peer-Reviewed Original ResearchTyrosine kinaseAcute lymphoblastic leukemiaAkt activityPre-B cell receptor signalingCell linesLeukemogenic tyrosine kinasesProtein target identificationKinase inhibitor screenImmunoblot analysisCell receptor signalingCell viabilityKinase inhibitor screeningClinical trial contractsReceptor tyrosine kinasesTyrosine kinase activityPhospho-protein arraysSmall molecule inhibitorsROR1 knockdownSiRNA screeningAkt regulationLymphoblastic leukemiaDasatinib treatmentKinase domainPatient costsLeukemia patientsTargeting Inhibitory Phosphatases in Tyrosine Kinase-Driven Leukemias
Shojaee S, Buchner M, Geng H, Silvia B, Koeffler P, Muschen M. Targeting Inhibitory Phosphatases in Tyrosine Kinase-Driven Leukemias. Blood 2011, 118: 1382. DOI: 10.1182/blood.v118.21.1382.1382.Peer-Reviewed Original ResearchCell deathReactive oxygen speciesInducible deletionLeukemia cellsTyrosine kinase signalingActivation signalsSmall molecule inhibitionSubsequent cell deathMultiple new targetsLeukemia cell deathBCR-ABL1 oncogeneCytoplasmic tailKinase signalingTransplant recipient miceInduction of CreTyrosine kinase inhibitorsCellular senescenceMolecule inhibitionTyrosine kinasePTPN6Drastic upregulationINPP5DCurrent tyrosine kinase inhibitorsPTENDeletion
2010
Mechanisms of Pre-B Cell Receptor-Inactivation In Acute Lymphoblastic Leukemia
Duy C, Nowak D, Klemm L, Nahar R, Ng C, Elliott E, Hofmann W, Heisterkamp N, Lowell C, Koeffler P, Muschen M. Mechanisms of Pre-B Cell Receptor-Inactivation In Acute Lymphoblastic Leukemia. Blood 2010, 116: 147. DOI: 10.1182/blood.v116.21.147.147.Peer-Reviewed Original ResearchPre-B cell receptorImmunoglobulin μ chainCell receptor functionCell receptor stimulationTyrosine kinasePAX5 fusion genesSystematic gene expression analysisΜ chainsSplice variantsCell receptorRapid cell cycle arrestExon 16Immunoglobulin gene rearrangementsReceptor functionReceptor signal transductionPre-B cell receptor functionGene rearrangementsGene expression analysisLeukemia cellsDominant-negative waySyk tyrosine kinaseCell cycle arrestPre B cellsSH2 domainMRNA splicingDominant-Negative Impact of PAX5/TEL on Downstream Targets of PAX5 and Essential Pre-B Cell Receptor Genes
Iwanski G, Thoennissen N, Nakitandwe J, Lin P, Kawamata N, Nahar R, Ramezani-Rad P, Chen S, Shurtleff S, Nowak D, Ruckert C, Dugas M, Bokemeyer C, Fazio G, Biondi A, Cazzaniga G, Downing J, Müschen M, Koeffler H. Dominant-Negative Impact of PAX5/TEL on Downstream Targets of PAX5 and Essential Pre-B Cell Receptor Genes. Blood 2010, 116: 3231. DOI: 10.1182/blood.v116.21.3231.3231.Peer-Reviewed Original ResearchB cell developmentPre-BCR signalingDominant-negative impactCell developmentTarget genesReporter constructsTyrosine kinasePre-B cell receptorPax5 target genesWild-type PAX5CCAAT/enhancer binding protein alphaBruton's agammaglobulinemia tyrosine kinaseTranscription factor Pax5Downstream target genesGene expression profilesDominant negative roleBCR pathwayGene expression dataLuciferase reporter constructsEndogenous Pax5High expression levelsTranscriptional activationAffymetrix HG-U133Downstream genesExpression of PAX5ROR1 as a Therapeutic Target In E2A-PBX1-Positive Acute Lymphoblastic Leukemia
Bicocca V, Chang B, Muschen M, Druker B, Tyner J. ROR1 as a Therapeutic Target In E2A-PBX1-Positive Acute Lymphoblastic Leukemia. Blood 2010, 116: 539. DOI: 10.1182/blood.v116.21.539.539.Peer-Reviewed Original ResearchReceptor tyrosine kinase-like orphan receptor 1Acute lymphoblastic leukemiaPositive cell linesLymphoblastic leukemiaMononuclear cellsLeukemia patientsE2A-PBX1Cytogenetic subtypesCell linesPatient samplesPositive acute lymphoblastic leukemiaKinase inhibitorsB-cell precursor phenotypeTyrosine kinaseCommon pediatric cancerKinase-like orphan receptor 1Novel therapeutic toolTyrosine kinase expressionKinase inhibitor dasatinibOrphan receptor 1Aberrant tyrosine kinase activityCell viabilityMTS cell viability assaysPrimary cellsPathogenesis of leukemia
2005
Mimicry of a constitutively active pre–B cell receptor in acute lymphoblastic leukemia cells
Feldhahn N, Klein F, Mooster JL, Hadweh P, Sprangers M, Wartenberg M, Bekhite MM, Hofmann WK, Herzog S, Jumaa H, Rowley JD, Müschen M. Mimicry of a constitutively active pre–B cell receptor in acute lymphoblastic leukemia cells. Journal Of Experimental Medicine 2005, 201: 1837-1852. PMID: 15939795, PMCID: PMC2213268, DOI: 10.1084/jem.20042101.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedCalcium SignalingCell Line, TumorCell SurvivalChildChild, PreschoolFemaleGene Expression Regulation, LeukemicHumansMaleMembrane GlycoproteinsMiddle AgedMolecular MimicryPre-B Cell ReceptorsPrecursor Cell Lymphoblastic Leukemia-LymphomaProtein-Tyrosine KinasesReceptors, Antigen, B-CellConceptsBruton's tyrosine kinaseBCR-ABL1Pre-B cell receptorCell receptorFull‐length Bruton tyrosine kinaseSurvival signalsAcute lymphoblastic leukemia cellsLeukemia cellsBCR-ABL1 kinase activityLymphoblastic leukemia cellsDownstream survival signalsBCR-ABL1 kinaseTyrosine kinaseCell receptor engagementKinase activityBypass selectionSTAT5 phosphorylationSrc homology domain 3BTK activityReceptorsAutonomous Ca2Receptor engagementSimilar extentActivation of PLCgamma1Dependent activation