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 BCL6Pharmacological Targeting of PI3K-Dependent Central Tolerance Mechanisms in Refractory Pre-Germinal Center B-Cell Malignancies
Kume K, Lee J, Chan L, Robinson M, Cosgun K, Meffre E, Müschen M. Pharmacological Targeting of PI3K-Dependent Central Tolerance Mechanisms in Refractory Pre-Germinal Center B-Cell Malignancies. Blood 2021, 138: 2267. DOI: 10.1182/blood-2021-149806.Peer-Reviewed Original ResearchCentral tolerance mechanismsMantle cell lymphomaB-cell malignanciesAutoreactive B cellsB cellsB cell developmentB cell receptorEarly B cell developmentB-ALLClinical cohortPharmacological targetingPathological signalingU-CLLNormal B-cell activationAutoreactive B cell receptorsRefractory B-ALLSequential treatment regimensPI3KNegative B cell selectionChronic lymphocytic leukemiaLarge clinical cohortB cell activationB-cell tumorsHuman B lymphopoiesisB cell selection
2019
Co-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 leukemia
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 transduction
2016
Correction: Corrigendum: Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia
Chen Z, Shojaee S, Buchner M, Geng H, Lee J, Klemm L, Titz B, Graeber T, Park E, Tan Y, Satterthwaite A, Paietta E, Hunger S, Willman C, Melnick A, Loh M, Jung J, Coligan J, Bolland S, Mak T, Limnander A, Jumaa H, Reth M, Weiss A, Lowell C, Müschen M. Correction: Corrigendum: Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia. Nature 2016, 534: 138-138. PMID: 26958840, DOI: 10.1038/nature16997.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 outcomeSignalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia
Chen Z, Shojaee S, Buchner M, Geng H, Lee JW, Klemm L, Titz B, Graeber TG, Park E, Tan YX, Satterthwaite A, Paietta E, Hunger SP, Willman CL, Melnick A, Loh ML, Jung JU, Coligan JE, Bolland S, Mak TW, Limnander A, Jumaa H, Reth M, Weiss A, Lowell CA, Müschen M. Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia. Nature 2015, 521: 357-361. PMID: 25799995, PMCID: PMC4441554, DOI: 10.1038/nature14231.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAnimalsAntigens, CDB-LymphocytesCell DeathCell Line, TumorCell Transformation, NeoplasticDisease Models, AnimalDrug Resistance, NeoplasmEnzyme ActivationFemaleFusion Proteins, bcr-ablGene DeletionHumansInositol Polyphosphate 5-PhosphatasesIntracellular Signaling Peptides and ProteinsMiceMice, Inbred NODMice, SCIDPhosphatidylinositol-3,4,5-Trisphosphate 5-PhosphatasesPhosphoric Monoester HydrolasesPlatelet Endothelial Cell Adhesion Molecule-1Precursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidProtein Tyrosine Phosphatase, Non-Receptor Type 6Protein-Tyrosine KinasesReceptors, Antigen, B-CellReceptors, ImmunologicSignal TransductionSyk KinaseTyrosineXenograft Model Antitumor Assays
2014
Harnessing Negative B Cell Selection to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia
Chen Z, Shojaee S, Geng H, Lee J, Buchner M, Klemm L, Lowell C, Paietta E, Willman C, Carroll W, Melnick A, Jung J, Jumaa H, Coligan J, Bolland S, Mak T, Muschen M. Harnessing Negative B Cell Selection to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia. Blood 2014, 124: 792. DOI: 10.1182/blood.v124.21.792.792.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaTyrosine kinase inhibitorsB cell receptorInhibitory receptorsTherapeutic targetPre-BCR signalingLymphoblastic leukemiaXenograft cellsB cellsSurvival rateB-cell acute lymphoblastic leukemiaCell deathAuto-reactive clonesFree survival rateCell acute lymphoblastic leukemiaOverall survival rateWorse clinical outcomesLeukemia cellsNegative B cell selectionAdditional therapeutic targetsAvailable therapeutic interventionsG1cell cycle arrestPotent tyrosine kinase inhibitorNovel small molecule inhibitorColony formation capacity