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
2018
B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies
Xiao G, Chan LN, Klemm L, Braas D, Chen Z, Geng H, Zhang QC, Aghajanirefah A, Cosgun KN, Sadras T, Lee J, Mirzapoiazova T, Salgia R, Ernst T, Hochhaus A, Jumaa H, Jiang X, Weinstock DM, Graeber TG, Müschen M. B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies. Cell 2018, 173: 470-484.e18. PMID: 29551267, PMCID: PMC6284818, DOI: 10.1016/j.cell.2018.02.048.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesCarbonCell Line, TumorCell SurvivalGlucoseGlucosephosphate DehydrogenaseGlycolysisHumansIkaros Transcription FactorMiceMice, Inbred C57BLMice, Inbred NODOxidative StressPAX5 Transcription FactorPentose Phosphate PathwayPrecursor Cell Lymphoblastic Leukemia-LymphomaProtein Phosphatase 2Proto-Oncogene Proteins c-bcl-2Transcription, GeneticConceptsPentose phosphate pathwayCarbon utilizationSerine/threonine protein phosphatase 2AB-cell transcription factor PAX5Transcription factor Pax5Favor of glycolysisSmall molecule inhibitionPhosphatase 2ATranscriptional repressionRedox homeostasisOncogenic transformationTumor suppressorMolecule inhibitionPP2AGenetic studiesPhosphate pathwayB cell activationEssential roleB-cell malignanciesCell malignanciesB cellsAntioxidant protectionOxidative stressB-cell tumorsCell activation
2015
Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia
Swaminathan S, Klemm L, Park E, Papaemmanuil E, Ford A, Kweon SM, Trageser D, Hasselfeld B, Henke N, Mooster J, Geng H, Schwarz K, Kogan SC, Casellas R, Schatz DG, Lieber MR, Greaves MF, Müschen M. Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nature Immunology 2015, 16: 766-774. PMID: 25985233, PMCID: PMC4475638, DOI: 10.1038/ni.3160.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAnimalsAntibody DiversityB-LymphocytesChildChild, PreschoolClonal EvolutionCytidine DeaminaseDNA-Binding ProteinsFemaleFlow CytometryHomeodomain ProteinsHumansImmunoblottingInfantMaleMice, Inbred NODMice, KnockoutMice, SCIDMice, TransgenicMicroscopy, FluorescencePrecursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidReverse Transcriptase Polymerase Chain ReactionTumor Cells, CulturedSignalling 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
2013
Both CpG Methylation and Activation-Induced Deaminase Are Required for the Fragility of the Human bcl-2 Major Breakpoint Region: Implications for the Timing of the Breaks in the t(14;18) Translocation
Cui X, Lu Z, Kurosawa A, Klemm L, Bagshaw AT, Tsai AG, Gemmell N, Müschen M, Adachi N, Hsieh CL, Lieber MR. Both CpG Methylation and Activation-Induced Deaminase Are Required for the Fragility of the Human bcl-2 Major Breakpoint Region: Implications for the Timing of the Breaks in the t(14;18) Translocation. Molecular And Cellular Biology 2013, 33: 947-957. PMID: 23263985, PMCID: PMC3623081, DOI: 10.1128/mcb.01436-12.Peer-Reviewed Original ResearchB-LymphocytesCell LineChromosome BreakpointsChromosomes, Human, Pair 14Chromosomes, Human, Pair 18CpG IslandsCytidine DeaminaseDNADNA MethylationDNA-Binding ProteinsEndonucleasesGene Knockout TechniquesGenes, bcl-2Homeodomain ProteinsHumansNuclear ProteinsProto-Oncogene Proteins c-bcl-2Translocation, Genetic
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 FactorsAnimalsApoptosisBase SequenceB-LymphocytesCell 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
The B Cell Mutator AID Promotes B Lymphoid Blast Crisis and Drug Resistance in Chronic Myeloid Leukemia
Klemm L, Duy C, Iacobucci I, Kuchen S, von Levetzow G, Feldhahn N, Henke N, Li Z, Hoffmann TK, Kim YM, Hofmann WK, Jumaa H, Groffen J, Heisterkamp N, Martinelli G, Lieber MR, Casellas R, Müschen M. The B Cell Mutator AID Promotes B Lymphoid Blast Crisis and Drug Resistance in Chronic Myeloid Leukemia. Cancer Cell 2009, 16: 232-245. PMID: 19732723, PMCID: PMC2931825, DOI: 10.1016/j.ccr.2009.07.030.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzamidesBlast CrisisB-LymphocytesCell Line, TumorCytidine DeaminaseDrug Resistance, NeoplasmFusion Proteins, bcr-ablGreen Fluorescent ProteinsHumansImatinib MesylateLeukemia, Myelogenous, Chronic, BCR-ABL PositiveLuciferases, RenillaMiceMice, Inbred BALB CMice, KnockoutMice, SCIDMice, TransgenicMutationPiperazinesPyrimidinesXenograft Model Antitumor AssaysConceptsLymphoid blast crisisChronic myeloid leukemiaB-lymphoid blast crisisBCR-ABL1 mutationsDrug resistanceMyeloid leukemiaBlast crisisCML cellsMechanisms of progressionImatinib resistanceClinical significanceBCR-ABL1Causative roleDNA repair genesLeukemia cellsRepair genesLeukemiaTumor suppressorAID expressionOverall genetic instabilityProgressionCellsGenetic instabilityImatinibMutations