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 proteinIFITM3
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 inactivation
2010
BCL6 is critical for the development of a diverse primary B cell repertoire
Duy C, Yu JJ, Nahar R, Swaminathan S, Kweon SM, Polo JM, Valls E, Klemm L, Shojaee S, Cerchietti L, Schuh W, Jäck HM, Hurtz C, Ramezani-Rad P, Herzog S, Jumaa H, Koeffler HP, de Alborán IM, Melnick AM, Ye BH, Müschen M. BCL6 is critical for the development of a diverse primary B cell repertoire. Journal Of Experimental Medicine 2010, 207: 1209-1221. PMID: 20498019, PMCID: PMC2882829, DOI: 10.1084/jem.20091299.Peer-Reviewed Original ResearchMeSH KeywordsADP-Ribosylation FactorsAnimalsApoptosisB-LymphocytesBase SequenceCell ProliferationCell SurvivalCells, CulturedCytoprotectionDNA DamageDNA-Binding ProteinsDown-RegulationGene Rearrangement, B-Lymphocyte, Light ChainHumansInterleukin-7LymphopoiesisMiceMolecular Sequence DataPre-B Cell ReceptorsPrecursor Cells, B-LymphoidProto-Oncogene Proteins c-bcl-6Proto-Oncogene Proteins c-mycRecombination, GeneticSignal TransductionTranscription, GeneticUp-RegulationConceptsDNA damage-induced apoptosisDamage-induced apoptosisImmunoglobulin light chain gene recombinationPre-B cell receptorBone marrow immature B cellsB cell developmentClass switch recombinationAbsence of Bcl6B cell repertoireExpression of BCL6Immature B cellsMu heavy chainDNA breaksNegative regulationPrimary B-cell repertoireGene recombinationCell developmentClonal diversityB cellsGerminal center B cellsSomatic hypermutationB cell precursorsExpression levelsBCL6 expressionCell precursors
2009
Pre–B cell receptor–mediated cell cycle arrest in Philadelphia chromosome–positive acute lymphoblastic leukemia requires IKAROS function
Trageser D, Iacobucci I, Nahar R, Duy C, von Levetzow G, Klemm L, Park E, Schuh W, Gruber T, Herzog S, Kim YM, Hofmann WK, Li A, Storlazzi CT, Jäck HM, Groffen J, Martinelli G, Heisterkamp N, Jumaa H, Müschen M. Pre–B cell receptor–mediated cell cycle arrest in Philadelphia chromosome–positive acute lymphoblastic leukemia requires IKAROS function. Journal Of Experimental Medicine 2009, 206: 1739-1753. PMID: 19620627, PMCID: PMC2722172, DOI: 10.1084/jem.20090004.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdultAnimalsCell CycleCell Transformation, NeoplasticDown-RegulationGene DeletionGenes, ablHumansIkaros Transcription FactorLeukemia, Prolymphocytic, B-CellMiceMice, KnockoutMice, TransgenicPhiladelphia ChromosomePre-B Cell ReceptorsSignal TransductionConceptsAcute lymphoblastic leukemiaCell cycle arrestPre-B cell receptorCell receptorLymphoblastic leukemiaPre-B cell receptor functionPhiladelphia chromosome-positive acute lymphoblastic leukemiaB-cell lineage acute lymphoblastic leukemiaCycle arrestUnfavorable clinical outcomeBCR-ABL1 tyrosine kinaseB cell precursorsCase of adultsBCR-ABL1 kinaseTumor suppressionClinical outcomesReceptor functionCell precursorsCell receptor functionIkaros functionCell cycle exitDownstream moleculesReceptorsLeukemiaSubtypes