2018
Ras-Driven B-Cell Transformation Targets Developmental Rewiring of Cytokine to Pre-B Cell Receptor Signaling
Chan L, Hurtz C, Geng H, Auer F, Chen Z, Xiao G, Lee J, Cosgun K, Ye B, Muschen M. Ras-Driven B-Cell Transformation Targets Developmental Rewiring of Cytokine to Pre-B Cell Receptor Signaling. Blood 2018, 132: 1336. DOI: 10.1182/blood-2018-99-115514.Peer-Reviewed Original ResearchPre-BCR signalingOncogenic Ras signalingOncogene-induced senescencePotential therapeutic intervention pointsCompetitive growth assaysInducible activationTherapeutic intervention pointCytokine receptorsRas signalingOncogenic RasPre-B cell receptor signalingCell transitionGenetic studiesPre-B cell receptorPre-B cell transitionIrreversible cell cycle arrestEarly B cell developmentLight chain gene expressionCell receptor signalingB cell developmentARF/p53Number of coloniesChain gene expressionDepletion of cellsCell cycle arrest
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
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 patientsPre-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-catenin
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 lesionsInactivation of Pre-B Cell Receptor-Mediated Tumor Suppression by Aberrant Splicing in Ph+ Acute Lymphoblastic Leukemia.
Duy C, Sprangers M, Klemm L, Nahar R, Nowak D, Martinelli G, Hofmann W, Koeffler P, Jumaa H, Müschen M. Inactivation of Pre-B Cell Receptor-Mediated Tumor Suppression by Aberrant Splicing in Ph+ Acute Lymphoblastic Leukemia. Blood 2009, 114: 579. DOI: 10.1182/blood.v114.22.579.579.Peer-Reviewed Original ResearchPre-B cell receptorSH2 domainSplice factorsTumor suppressor functionAberrant splicingSplice variantsPre-B cell receptor signalingSequence analysisSplice siteSplice site mutationExon 16Suppressor functionCell receptorImportant protein domainsFunctional SH2 domainSite mutationSplice site selectionDetailed sequence analysisCell receptor signalingDominant negative effectDownstream effector moleculesCell linesMultiple splice variantsSplicing factorsProtein domains
2008
Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1
Trageser D, Duy C, Klemm L, Gruber T, Nahar R, Park E, Kim Y, Groffen J, Heisterkamp N, Hofmann W, Martinelli G, Williams R, Jumaa H, Muschen M. Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1. Blood 2008, 112: 15. DOI: 10.1182/blood.v112.11.15.15.Peer-Reviewed Original ResearchFunctional pre-B cell receptorAcute lymphoblastic leukemiaBCR-ABL1Pre-B cell receptorCell receptorBone marrowPre-B cell receptor functionTransgenic miceLeukemic transformationLeukemic growthNOD/SCID miceWeight lossLeukemia cellsReceptor selectionTransgenic mouse modelSignificant weight lossPre-B cell receptor signalingBCR-ABL1 expressionSigns of diseaseSurvival signalsEarly B cell developmentLeukemic infiltrationSplenic enlargementCell receptor signalingPeripheral bloodThe 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 oncogeneAberrant Splicing of the SLP65 SH2 Domain Enables Pre-B Cell Transformation and Compromises the Leukemia-Suppressive Function of the Pre-B Cell Receptor
Duy C, Klemm L, Nahar R, van Essen P, Sprangers M, Kim Y, Park E, Martinelli G, Heisterkamp N, Hofmann W, Jumaa H, Muschen M. Aberrant Splicing of the SLP65 SH2 Domain Enables Pre-B Cell Transformation and Compromises the Leukemia-Suppressive Function of the Pre-B Cell Receptor. Blood 2008, 112: 294. DOI: 10.1182/blood.v112.11.294.294.Peer-Reviewed Original ResearchBCR-ABL1Pre-B cell receptorEarly pre-B cell stageCell receptorPre-B cell stageNOD/SCID miceLeukemia cellsPre-B cell receptor signalingSigns of diseaseSplice variantsEarly B cell developmentLeukemic infiltrationQuantitative RT-PCRCell receptor signalingCell receptor engagementSCID miceBone marrowB cell developmentMalignant transformationPre-B-cell transformationLeukemic growthCell transformationInduction of differentiationGermline mutationsMice
2007
Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1.
Trageser D, Klemm L, Herzog S, Kim Y, Duy C, Hofmann W, Groffen J, Heisterkamp N, Jumaa H, Muschen M. Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1. Blood 2007, 110: 2795. DOI: 10.1182/blood.v110.11.2795.2795.Peer-Reviewed Original ResearchPre-B cell receptorFunctional pre-B cell receptorImmunoglobulin heavy chain locusAcute lymphoblastic leukemiaBCR-ABL1Cell receptorSurvival signalsPre-B cell receptor signalingReceptor selectionEarly B cell developmentBone marrowPre-B cell receptor functionTransgenic miceLeukemic transformationCell receptor signalingRapid cell deathB cell developmentHuman BCR-ABL1Potent tumor suppressorHeavy chain locusPre B cellsSingle-cell PCRTransgenic mouse modelCell receptor functionB cell precursors
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