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 outcomesCD25 recruits inhibitory phosphatases for feedback control of B-cell receptor signaling
Sun R, Lee J, Robinson M, Kume K, Cosgun K, Chan L, Leveille E, Geng H, Vykunta V, Shy B, Marson A, Meffre E, Müschen M. CD25 recruits inhibitory phosphatases for feedback control of B-cell receptor signaling. The Journal Of Immunology 2023, 210: 154.23-154.23. DOI: 10.4049/jimmunol.210.supp.154.23.Peer-Reviewed Original ResearchAntigen-experienced B cellsB cellsEarly B cell developmentGerminal centersB cell developmentSpontaneous germinal centersCD25 surface expressionAutoreactive B cellsRole of CD25B cell toleranceB-cell receptor signalingB-cell leukemiaB cell receptorAutoantibody productionCD25Cell toleranceGenetic ablationReceptor signalingBCR signalingOncogenic signalingInhibitorySuccessful initiationSignalingNegative selectionAutoimmunity
2016
Pre-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
Self-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
2011
Pre-B Cell Receptor-Mediated Activation of BCL6 Induces Pre-B Cell Quiescence Through Transcriptional Repression of MYC
Nahar R, Ramezani-Rad P, Mossner M, Duy C, Cerchietti L, Geng H, Jumaa H, Ye B, Melnick A, Muschen M. Pre-B Cell Receptor-Mediated Activation of BCL6 Induces Pre-B Cell Quiescence Through Transcriptional Repression of MYC. Blood 2011, 118: 1406. DOI: 10.1182/blood.v118.21.1406.1406.Peer-Reviewed Original ResearchPre-B cell receptorCell receptorCell cycle exitExit cell cycleInitial proliferative burstAcute lymphoblastic leukemiaCycle exitB cell precursorsPre-B cell receptor signalingInducible activationTranscriptional repressor BCL6Receptor-Mediated ActivationCell receptor signalingInduction of quiescenceLymphoblastic leukemiaCell surface expressionOverexpression of MYCCCND2 expressionCell cycleBcl6-deficient miceMalignant transformationReceptor signalingReceptors resultsCell precursorsReceptorsMechanisms of Ikaros-Mediated Tumor Suppression
Nahar R, Ramezani-Rad P, Dovat S, Buchner M, Graeber T, Muschen M. Mechanisms of Ikaros-Mediated Tumor Suppression. Blood 2011, 118: 408. DOI: 10.1182/blood.v118.21.408.408.Peer-Reviewed Original ResearchPre-B cell receptor signalingPre-B cell receptorCell receptor signalingAbility of IkarosGene expression changesTumor suppressor pathwayTumor suppressionTumor suppressorDephosphorylation eventsReceptor signalingGenetic evidenceSuppressor pathwayAdapter moleculeExpression changesCritical phosphorylation eventsCommon gene expression changesCell receptorTumor-suppressive transcription factorCell cycle exitSimilar gene expression changesComprehensive gene expression analysisARF/p53 pathwayLeukemia cellsBCR-ABL1 kinaseCell cycle progression
2010
Pre-B Cell Receptor Signaling Distinguishes E2A-PBX1 From Other Subtypes of Acute Lymphoblastic Leukemia
Nahar R, Trageser D, Klemm L, Duy C, Hofmann W, Park E, Kim Y, Heisterkamp N, Jumaa H, Muschen M. Pre-B Cell Receptor Signaling Distinguishes E2A-PBX1 From Other Subtypes of Acute Lymphoblastic Leukemia. Blood 2010, 116: 274. DOI: 10.1182/blood.v116.21.274.274.Peer-Reviewed Original ResearchPre-B cell receptorPre-B cell receptor signalingFunctional pre-B cell receptorEarly pre-B cell stageCanonical Wnt/β-catenin signalingPre-B cell stageCell receptor signalingWnt/β-catenin signalingCell receptor functionE2A-PBX1Β-catenin signalingBCR-ABL1 oncogeneCell stageB cell lineage commitmentCell receptorReceptor signalingPre-B cell receptor expressionEarly B cell developmentComparative gene expressionMLL-AF4Pre-B cell receptor functionCell lineage commitmentReceptor functionGene expression differencesCanonical Wnt/β-cateninSYK Is a Tumor Suppressor In Pre-B Cell Acute Lymphoblastic Leukemia and Not a Therapeutic Target
Ng C, Nahar R, Elliott E, Lowell C, Muschen M. SYK Is a Tumor Suppressor In Pre-B Cell Acute Lymphoblastic Leukemia and Not a Therapeutic Target. Blood 2010, 116: 4199. DOI: 10.1182/blood.v116.21.4199.4199.Peer-Reviewed Original ResearchDeletion of SykPre-B leukemia cellsAcute lymphoblastic leukemiaPre-B cell receptor functionB-cell lymphomaImatinib treatmentTumor-suppressive effectsRole of SykPre-B cell receptorCell cycle arrestBCR-ABL1Cell receptorCritical survival signalsLeukemia cellsCell receptor signalingLymphoblastic leukemiaCell lymphomaSuppressive effectCycle arrestSyk tyrosine kinaseReceptor functionPre-B-cell acute lymphoblastic leukemiaWestern blotReceptor signalingPre-B cell receptor expression
2009
The Pax5 Fusion Product Pax5-C20orf112 Causes Downregulation of Pre-B Cell Receptor Genes and Induces Differential Proliferation Patterns in B-Lymphoblastic Cell Lines.
Nowak D, Kawamata N, Niebuhr B, Nowak V, Mossner M, Nahar R, Thoennissen N, Iwanski G, Stocking C, Dugas M, Hofmann W, Müschen M, Koeffler P. The Pax5 Fusion Product Pax5-C20orf112 Causes Downregulation of Pre-B Cell Receptor Genes and Induces Differential Proliferation Patterns in B-Lymphoblastic Cell Lines. Blood 2009, 114: 1284. DOI: 10.1182/blood.v114.22.1284.1284.Peer-Reviewed Original ResearchPre-B cell receptor signalingPre-B cell receptorWild-type PAX5Cell receptor signalingImmunoglobulin heavy locusCandidate genesFusion productsCell linesFunctional pre-B cell receptorB-cell-specific transcription factor Pax5Spleen tyrosine kinaseGlobal gene expression analysisReceptor signalingPleckstrin homology domainRetroviral expression constructsB-cell linkerGroup of genesTranscription factor Pax5Promoter binding sitesAdaptor protein 1Receptor pathwayGene expression analysisEmpty vector controlGene expression microarraysCommon genomic lesions
2008
The Pre-B Cell Receptor Suppresses Leukemogenesis by Censoring MYC Expression.
Nahar R, Trageser D, Klemm L, Duy C, van Essen P, Kim Y, Heisterkamp N, Martinelli G, Hofmann W, Jack H, Jumaa H, Muschen M. The Pre-B Cell Receptor Suppresses Leukemogenesis by Censoring MYC Expression. Blood 2008, 112: 1918. DOI: 10.1182/blood.v112.11.1918.1918.Peer-Reviewed Original ResearchPre-B cell receptorPre-B cell receptor expressionPre-B cell receptor signalingFunctional pre-B cell receptorEarly pre-B cell stagePre-B cell stageCell receptor signalingSubstantial growth advantageB cell precursorsCell stageE2A-PBX1Receptor signalingCell receptorCell precursorsEarly B cell developmentGrowth advantageComparative gene expressionMYC expressionMLL-AF4Cell receptor expressionB cell developmentMYC mRNA levelsHeavy chain locusHigh expression levelsBCR-ABL1 oncogene
2004
The BCR-ABL1 Kinase Bypasses Selection for the Expression of a Pre–B Cell Receptor in Pre–B Acute Lymphoblastic Leukemia Cells
Klein F, Feldhahn N, Harder L, Wang H, Wartenberg M, Hofmann WK, Wernet P, Siebert R, Müschen M. The BCR-ABL1 Kinase Bypasses Selection for the Expression of a Pre–B Cell Receptor in Pre–B Acute Lymphoblastic Leukemia Cells. Journal Of Experimental Medicine 2004, 199: 673-685. PMID: 14993251, PMCID: PMC2213306, DOI: 10.1084/jem.20031637.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdolescentAdultAgedBase SequenceCarrier ProteinsChildChild, PreschoolDNA, NeoplasmFemaleFusion Proteins, bcr-ablGene ExpressionGene Rearrangement, B-Lymphocyte, Heavy ChainHumansMaleMembrane GlycoproteinsMiddle AgedPhosphoproteinsPre-B Cell ReceptorsPrecursor B-Cell Lymphoblastic Leukemia-LymphomaProtein-Tyrosine KinasesReceptors, Antigen, B-CellSelection, GeneticConceptsPre-B cell receptorVH region genesWide gene expression profilesPre-B cell receptor signalingFunctional B-cell receptorFunctional pre-B cell receptorCell receptorReceptor engagementAntigen receptor engagementLeukemia cellsCell receptor signalingGene expression profilesRegion genesCell receptor engagementBCR-ABL1 kinase activityB cell receptorImmature B cellsVH gene rearrangementsKinase activityGene expressionExpression profilesAcute lymphoblastic leukemiaReceptor signalingSerial analysisBCR-ABL1