2023
Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms
Taghi Khani A, Kumar A, Sanchez Ortiz A, Radecki K, Aramburo S, Lee S, Hu Z, Damirchi B, Lorenson M, Wu X, Gu Z, Stohl W, Sanz I, Meffre E, Müschen M, Forman S, Koff J, Walker A, Swaminathan S. Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms. Communications Biology 2023, 6: 295. PMID: 36941341, PMCID: PMC10027679, DOI: 10.1038/s42003-023-04667-8.Peer-Reviewed Original ResearchConceptsHuman B-cell malignanciesB-cell malignanciesB-cell neoplasmsB cellsPathogenic B cell subsetsPRL receptorsSLE-prone miceSystemic lupus erythematosusB cell numbersB cell subsetsB cell viabilityNormal B cellsExpression of Bcl2B cell survivalB-cell transformationLupus erythematosusLymphoproliferative diseaseAutocrine prolactinMouse modelPRLR isoformsMalignancyProlactinBCL2 expressionProlactin receptorIsoform-specific knockdown
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 BCL6Identification of a Conserved Intracellular Loop (CIL) Structure That Scaffolds PIP3 to Amplify Oncogenic Signaling during Malignant B-Cell Transformation
Lee J, Robinson M, Ma N, Sadras T, Cosgun K, Chan L, Kume K, Thomas-Tikhonenko A, Weinstock D, Diamond M, Vaidehi N, Müschen M. Identification of a Conserved Intracellular Loop (CIL) Structure That Scaffolds PIP3 to Amplify Oncogenic Signaling during Malignant B-Cell Transformation. Blood 2021, 138: 868. DOI: 10.1182/blood-2021-149646.Peer-Reviewed Original ResearchLipid raftsB cell receptorB cell activationB cell activation signalsConstitutive membrane localizationMalignant B-cell transformationPleckstrin homology domainCell membrane lipid compositionMembrane lipid compositionNormal B-cell activationEndosomal proteinCell membrane lipidsBasic lysine residueHomology domainPH domainMembrane localizationB-cell transformationProteomic analysisEndosomal membranesPIP3PIP3 accumulationOncogenic signalingOncogenic transformationGene expressionInducible activation
2020
Signalling input from divergent pathways subverts B cell transformation
Chan LN, Murakami MA, Robinson ME, Caeser R, Sadras T, Lee J, Cosgun KN, Kume K, Khairnar V, Xiao G, Ahmed MA, Aghania E, Deb G, Hurtz C, Shojaee S, Hong C, Pölönen P, Nix MA, Chen Z, Chen CW, Chen J, Vogt A, Heinäniemi M, Lohi O, Wiita AP, Izraeli S, Geng H, Weinstock DM, Müschen M. Signalling input from divergent pathways subverts B cell transformation. Nature 2020, 583: 845-851. PMID: 32699415, PMCID: PMC7394729, DOI: 10.1038/s41586-020-2513-4.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesCell Line, TumorCell Transformation, NeoplasticEnzyme ActivationExtracellular Signal-Regulated MAP KinasesFemaleHumansLeukemia, B-CellMiceProtein Tyrosine Phosphatase, Non-Receptor Type 6Proto-Oncogene Proteins c-bcl-6Proto-Oncogene Proteins c-mycSignal TransductionSTAT5 Transcription FactorConceptsPre-B cell receptorPrincipal oncogenic driverDivergent pathwaysSignal transduction proteinsPro-B cell stageSingle-cell mutationTranscription factor MYCOncogenic driversDivergent signaling pathwaysSingle oncogenic pathwayCentral oncogenic driverMore mature cellsGenetic reactivationTranscriptional programsB-cell transformationProtein kinasePathway componentsERK activationIndividual mutationsOncogenic STAT5Signaling pathwaysCell transformationCytokine receptorsGenetic lesionsDivergent circuits
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 agonistsIfitm3 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 transformationRationale 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 fusionMicroRNA-142 Is an Essential Negative Regulator of B Cell Maturation and Malignant Transformation
Graham N, Wang W, Magilnick N, Lee J, Wang H, Zhang B, Marcucci G, Muschen M, Reyes E, Boldin M. MicroRNA-142 Is an Essential Negative Regulator of B Cell Maturation and Malignant Transformation. The Journal Of Immunology 2019, 202: 53.22-53.22. DOI: 10.4049/jimmunol.202.supp.53.22.Peer-Reviewed Original ResearchMalignant B-cell transformationB cell developmentEμ-myc transgenic miceEssential negative regulatorB cell maturationNegative regulatorB-cell transformationMiR-142Transgenic miceCell developmentCell transformationB-cell lymphoblastic leukemiaCell maturationEarly B cell developmentPrimary B cell developmentEarly B cell progenitorsPre-B cell stageMature B cell compartmentB cell compartmentB cell progenitorsB-cell ontogenesisIL-7 stimulationImmature B cellsLymphoblastic leukemiaCell ontogenesisMetabolic 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
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 activity
2016
Transcriptional Control of Glucose and Energy Supply Prevents Oncogenic Signaling and B Cell Transformation
Chan L, Chen Z, Xiao G, Lee J, Geng H, Christian H, Cazzaniga V, Cazzaniga G, Dickins R, Müschen M. Transcriptional Control of Glucose and Energy Supply Prevents Oncogenic Signaling and B Cell Transformation. Blood 2016, 128: 437. DOI: 10.1182/blood.v128.22.437.437.Peer-Reviewed Original ResearchB-cell transcription factorsTranscription factorsCellular ATP levelsPositive regulatorOncogenic signalingNegative regulatorSurvival fitnessCRISPR/Cas9-mediated deletionWild-type PAX5Glucose uptakeQuantitative chromatin immunoprecipitationEffect of PAX5Regions of genesB cell identityProtein levelsCompetitive growth assaysATP levelsTumor suppressive functionSecondary genetic lesionsB-lineageChIPseq dataTranscriptional controlChromatin immunoprecipitationB-cell transformationPatient-derived preBCL6 Is Critical to Overcome Oncogene-Induced Senescence in RAS-Mediated B Cell Transformation
Chan L, Hurtz C, Xiao G, Shojaee S, Caeser R, Geng H, Melnick A, Müschen M. BCL6 Is Critical to Overcome Oncogene-Induced Senescence in RAS-Mediated B Cell Transformation. Blood 2016, 128: 438. DOI: 10.1182/blood.v128.22.438.438.Peer-Reviewed Original ResearchDiffuse large B-cell lymphomaRAS-ERK signalingBCL6 expressionRole of BCL6Recipient micePhiladelphia chromosome-positive acute lymphoblastic leukemiaSTAT5 activityRAS-ERKLarge B-cell lymphomaAbsence of Bcl6Acute lymphoblastic leukemiaNovel mouse modelProto-oncogene Bcl6B-cell lymphomaNovel therapeutic avenuesTransplant recipient miceNovel mechanismMouse embryonic fibroblastsOncogene-Induced SenescenceP53-dependent senescenceB-cell transformationInitial remissionLeukemia relapseOverall survivalImatinib treatment