2023
Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1‐EEF1A1 Axis
Li M, Yang L, Chan A, Pokharel S, Liu Q, Mattson N, Xu X, Chang W, Miyashita K, Singh P, Zhang L, Li M, Wu J, Wang J, Chen B, Chan L, Lee J, Zhang X, Rosen S, Müschen M, Qi J, Chen J, Hiom K, Bishop A, Chen C. Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1‐EEF1A1 Axis. Advanced Science 2023, 10: 2206584. PMID: 37075745, PMCID: PMC10265057, DOI: 10.1002/advs.202206584.Peer-Reviewed Original ResearchConceptsProtein translation machineryHistone H4 acetylationOncogenic transcription factorNuA4 histoneChromatin remodelersGene bodiesEpigenetic networksTranslation machineryATPase componentEpigenetic controlTumor progressionCRISPR screensTranscription factorsH4 acetylationEpigenetic dysregulationRUVBL1Oncogenic signalingProtein synthesisPatient-derived samplesMYCPharmacological inhibitionEEF1A1 expressionMultiple cancersNovel opportunitiesDynamic interplayPhosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia
Chen Z, Zhou K, Xue J, Small A, Xiao G, Nguyen L, Zhang Z, Prince E, Weng H, Huang H, Zhao Z, Qing Y, Shen C, Li W, Han L, Tan B, Su R, Qin H, Li Y, Wu D, Gu Z, Ngo V, He X, Chao J, Leung K, Wang K, Dong L, Qin X, Cai Z, Sheng Y, Chen Y, Wu X, Zhang B, Shi Y, Marcucci G, Qian Z, Xu M, Müschen M, Chen J, Deng X. Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia. Science Translational Medicine 2023, 15: eabq8513. PMID: 36989375, PMCID: PMC11163962, DOI: 10.1126/scitranslmed.abq8513.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDNA-Binding ProteinsMicePhosphorylationPrecursor Cell Lymphoblastic Leukemia-LymphomaProto-Oncogene ProteinsSignal TransductionStaurosporineConceptsB-cell acute lymphoblastic leukemiaCell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaB-ALLRefractory/Oncogenic roleLymphoblastic leukemiaProtein kinase C epsilonOverall survival rateNormal precursor B cellsCrucial oncogenic rolePrecursor B cellsAdult patientsPDX modelsPharmacological targetingTherapeutic targetB cellsImproved therapiesSurvival rateLeukemia progressionTherapeutic potentialOverexpression of TET1TET1 proteinATM serine/threonine kinaseLeukemia
2021
Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer
Sadras T, Martin M, Kume K, Robinson ME, Saravanakumar S, Lenz G, Chen Z, Song JY, Siddiqi T, Oksa L, Knapp AM, Cutler J, Cosgun KN, Klemm L, Ecker V, Winchester J, Ghergus D, Soulas-Sprauel P, Kiefer F, Heisterkamp N, Pandey A, Ngo V, Wang L, Jumaa H, Buchner M, Ruland J, Chan WC, Meffre E, Martin T, Müschen M. Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer. Molecular Cell 2021, 81: 2094-2111.e9. PMID: 33878293, PMCID: PMC8239336, DOI: 10.1016/j.molcel.2021.03.043.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CD19AutoimmunityB-LymphocytesCalciumCell DifferentiationCell Transformation, NeoplasticEnzyme ActivationHumansImmune ToleranceLymphoma, B-CellMiceModels, GeneticNeoplasm ProteinsNeoplasmsNFATC Transcription FactorsPhosphatidylinositol 3-KinasesProtein BindingReceptors, Antigen, B-CellSignal TransductionSyk KinaseZAP-70 Protein-Tyrosine Kinase
2020
IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells
Lee J, Robinson ME, Ma N, Artadji D, Ahmed MA, Xiao G, Sadras T, Deb G, Winchester J, Cosgun KN, Geng H, Chan LN, Kume K, Miettinen TP, Zhang Y, Nix MA, Klemm L, Chen CW, Chen J, Khairnar V, Wiita AP, Thomas-Tikhonenko A, Farzan M, Jung JU, Weinstock DM, Manalis SR, Diamond MS, Vaidehi N, Müschen M. IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells. Nature 2020, 588: 491-497. PMID: 33149299, PMCID: PMC8087162, DOI: 10.1038/s41586-020-2884-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CD19B-LymphocytesCell Transformation, NeoplasticFemaleGerminal CenterHumansIntegrinsMembrane MicrodomainsMembrane ProteinsMiceMice, Inbred C57BLMice, Inbred NODModels, MolecularPhosphatidylinositol 3-KinasesPhosphatidylinositol PhosphatesPhosphorylationReceptors, Antigen, B-CellRNA-Binding ProteinsSignal TransductionConceptsPI3KCell leukemiaAntiviral effector functionsAntigen-specific antibodiesInterferon-induced transmembrane proteinsIFITM3 functionDevelopment of leukemiaCell surfacePoor outcomeOncogenic PI3KClinical cohortEffector functionsGerminal centersMouse modelB cellsExpression of IFITM3Malignant transformationAccumulation of PIP3PI3K signalsCell receptorNormal numbersLeukemiaDefective expressionEndosomal proteinIFITM3Signalling 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
2017
Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia
Takao S, Chien W, Madan V, Lin D, Ding L, Sun Q, Mayakonda A, Sudo M, Xu L, Chen Y, Jiang Y, Gery S, Lill M, Park E, Senapedis W, Baloglu E, Müschen M, Koeffler H. Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia. Leukemia 2017, 32: 616-625. PMID: 28904384, DOI: 10.1038/leu.2017.281.Peer-Reviewed Original ResearchMeSH KeywordsAcrylamidesAminopyridinesAnimalsAntineoplastic AgentsApoptosisCell Line, TumorCell ProliferationCell SurvivalCytokinesDisease Models, AnimalFemaleHumansMaleMiceNADNicotinamide PhosphoribosyltransferaseP21-Activated KinasesPrecursor B-Cell Lymphoblastic Leukemia-LymphomaSignal TransductionXenograft Model Antitumor AssaysConceptsB-cell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaP21-activated kinase 4Nicotinamide phosphoribosyltransferaseLymphoblastic leukemiaNAMPT inhibitionPatient-derived xenograft murine modelsPrognosis of patientsNicotinamide adenine dinucleotideNovel therapeutic strategiesNicotinic acid supplementationNovel dual inhibitorXenograft murine modelCell growth inhibitionAcid supplementationMurine modelTherapeutic strategiesRate-limiting enzymeCytogenetic abnormalitiesVivo efficacyPatientsNAMPT inhibitorsInhibitory effectDual inhibitorKinase 4Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival
Katerndahl CDS, Heltemes-Harris LM, Willette MJL, Henzler CM, Frietze S, Yang R, Schjerven H, Silverstein KAT, Ramsey LB, Hubbard G, Wells AD, Kuiper RP, Scheijen B, van Leeuwen FN, Müschen M, Kornblau SM, Farrar MA. Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival. Nature Immunology 2017, 18: 694-704. PMID: 28369050, PMCID: PMC5540372, DOI: 10.1038/ni.3716.Peer-Reviewed Original ResearchAdaptor Proteins, Signal TransducingAgammaglobulinaemia Tyrosine KinaseAnimalsB-LymphocytesChromatin ImmunoprecipitationFlow CytometryGene Expression Regulation, NeoplasticHumansIkaros Transcription FactorInterferon Regulatory FactorsMiceMultiplex Polymerase Chain ReactionNF-kappa B p50 SubunitPAX5 Transcription FactorPre-B Cell ReceptorsPrecursor Cell Lymphoblastic Leukemia-LymphomaPrognosisProtein Kinase C betaProtein-Tyrosine KinasesProto-Oncogene ProteinsReal-Time Polymerase Chain ReactionSignal TransductionSTAT5 Transcription FactorSurvival RateTrans-Activators
2016
PTEN opposes negative selection and enables oncogenic transformation of pre-B cells
Shojaee S, Chan LN, Buchner M, Cazzaniga V, Cosgun KN, Geng H, Qiu YH, von Minden MD, Ernst T, Hochhaus A, Cazzaniga G, Melnick A, Kornblau SM, Graeber TG, Wu H, Jumaa H, Müschen M. PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nature Medicine 2016, 22: 379-387. PMID: 26974310, PMCID: PMC5178869, DOI: 10.1038/nm.4062.Peer-Reviewed Original ResearchPre-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
Signalling 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 AssaysIdentification 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 inactivationSelf-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
2006
The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells
Sprangers M, Feldhahn N, Herzog S, Hansmann M, Reppel M, Hescheler J, Jumaa H, Siebert R, Müschen M. The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells. Oncogene 2006, 25: 5056-5062. PMID: 16568084, DOI: 10.1038/sj.onc.1209510.Peer-Reviewed Original ResearchConceptsB-cell lymphoma cellsB cell receptor engagementCell lymphoma cellsSrc kinase LynCell receptor engagementB cell receptorKinase LynReceptor-induced Ca2Lymphoma cellsCell receptorReceptor engagementB-cell receptor signal transductionSrc family kinase LynB-cell-derived lymphomasSrc kinase activityReceptor signal transductionAcute lymphoblastic leukemiaSrc kinase activationProliferation-related moleculesB-cell lymphoma casesReceptor-dependent Ca2Normal B cellsActivation of survivalSignal transductionRNA interference
2000
Somatic Mutation of the Cd95 Gene in Human B Cells as a Side-Effect of the Germinal Center Reaction
Müschen M, Re D, Jungnickel B, Diehl V, Rajewsky K, Küppers R. Somatic Mutation of the Cd95 Gene in Human B Cells as a Side-Effect of the Germinal Center Reaction. Journal Of Experimental Medicine 2000, 192: 1833-1840. PMID: 11120779, PMCID: PMC2213498, DOI: 10.1084/jem.192.12.1833.Peer-Reviewed Original ResearchConceptsDeath domainCD95 geneSomatic mutationsNegative selectionNon-Ig genesHuman B cellsSomatic hypermutation machineryApoptosis-resistant cellsTumor suppressor geneDD mutationsLast exonHypermutation machinerySuppressor geneApoptosis resistanceGenesB cellsImmunoglobulin genesGerminal center B cellsSomatic hypermutationMutationsCD95 pathwayGC B-cell lymphomasGC B cellsCellsGerminal center reaction