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 Assays
2013
AID downregulation is a novel function of the DNMT inhibitor 5-aza-deoxycytidine
Tsai CT, Yang PM, Chern TR, Chuang SH, Lin JH, Klemm L, Müschen M, Chen CC. AID downregulation is a novel function of the DNMT inhibitor 5-aza-deoxycytidine. Oncotarget 2013, 5: 211-223. PMID: 24457556, PMCID: PMC3960202, DOI: 10.18632/oncotarget.1319.Peer-Reviewed Original ResearchConceptsActivation-induced cytidine deaminaseClass switch recombinationTumor suppressor geneHematopoietic cancer cellsAID expressionSomatic hypermutationNovel biological functionDNMT inhibitor 5Cancer cellsHost genesProteasomal degradationDNMT inhibitorsNovel functionBiological functionsInhibitor 5Suppressor geneSwitch recombinationImmunoglobulin genesCancer progressionCytidine deaminaseGenesDNMT1ZEBMolecular dockingActive siteSmall-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia
Gang EJ, Hsieh YT, Pham J, Zhao Y, Nguyen C, Huantes S, Park E, Naing K, Klemm L, Swaminathan S, Conway EM, Pelus LM, Crispino J, Mullighan CG, McMillan M, Müschen M, Kahn M, Kim YM. Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. Oncogene 2013, 33: 2169-2178. PMID: 23728349, PMCID: PMC3994178, DOI: 10.1038/onc.2013.169.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsAsparaginaseBeta CateninBridged Bicyclo Compounds, HeterocyclicCell Line, TumorCell ProliferationCell SurvivalDexamethasoneDown-RegulationDrug Resistance, NeoplasmDrug SynergismHumansInhibitor of Apoptosis ProteinsMiceMice, Inbred NODMice, SCIDMutationPeptide FragmentsPrecursor Cell Lymphoblastic Leukemia-LymphomaPyrimidinonesSialoglycoproteinsSurvivinVincristineWnt Signaling PathwayXenograft Model Antitumor AssaysConceptsICG-001Activation of genesDivergent cellular responsesProgenitor cellsInitiation of differentiationSmall molecule modulatorsAcute lymphoblastic leukemiaAmino acids 1Small molecule inhibitionWnt/cateninNovel small molecule modulatorsPrimary acute lymphoblastic leukemiaCoactivator CBPChromatin immunoprecipitationTranscriptional activationHematopoietic progenitor cellsSelf-renewal capacityApoptosis proteinNormal hematopoietic progenitor cellsCBP mutationsN-terminusCellular responsesCatenin interactionC-terminalSurvivin promoterIntegrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy
Hsieh YT, Gang EJ, Geng H, Park E, Huantes S, Chudziak D, Dauber K, Schaefer P, Scharman C, Shimada H, Shojaee S, Klemm L, Parameswaran R, Loh M, Kang ES, Koo HH, Hofmann WK, Andrade J, Crooks GM, Willman CL, Müschen M, Papayannopoulou T, Heisterkamp N, Bönig H, Kim YM. Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy. Blood 2013, 121: 1814-1818. PMID: 23319569, PMCID: PMC3591800, DOI: 10.1182/blood-2012-01-406272.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, Monoclonal, HumanizedBone MarrowCell AdhesionChildDrug Resistance, NeoplasmFlow CytometryFusion Proteins, bcr-ablHumansIntegrasesIntegrin alpha4MiceMice, Inbred NODMice, KnockoutMice, SCIDNatalizumabNeoplasm, ResidualPrecursor B-Cell Lymphoblastic Leukemia-LymphomaReal-Time Polymerase Chain ReactionReverse Transcriptase Polymerase Chain ReactionRNA, MessengerStromal CellsConceptsBone marrowMalignant B-cell precursorsNOD/SCID recipientsAcute lymphoblastic leukemia cellsLeukemia cellsAcute lymphoblastic leukemiaLack of efficacyMinimal residual diseaseLymphoblastic leukemia cellsB cell precursorsModels of leukemiaSCID recipientsPoor outcomeResidual diseaseCurrent therapiesLymphoblastic leukemiaChemotherapyConditional deletionBlockadeIntegrin alpha4LeukemiaGene expression analysisCellsAlpha4Novel strategy
2011
Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia
Park E, Gang EJ, Hsieh YT, Schaefer P, Chae S, Klemm L, Huantes S, Loh M, Conway EM, Kang ES, Koo H, Hofmann WK, Heisterkamp N, Pelus L, Keerthivasan G, Crispino J, Kahn M, Müschen M, Kim YM. Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia. Blood 2011, 118: 2191-2199. PMID: 21715311, PMCID: PMC3162353, DOI: 10.1182/blood-2011-04-351239.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCombined Modality TherapyDrug Resistance, NeoplasmGene ExpressionGene TargetingHumansInhibitor of Apoptosis ProteinsMiceMice, Inbred NODMice, KnockoutNeoplasm, ResidualOligonucleotidesPrecursor Cell Lymphoblastic Leukemia-LymphomaRepressor ProteinsRNA, Small InterferingSurvivinTumor Stem Cell AssayXenograft Model Antitumor AssaysConceptsAcute lymphoblastic leukemiaDrug resistanceLymphoblastic leukemiaDrug-resistant acute lymphoblastic leukemiaDetectable minimal residual diseasePrimary acute lymphoblastic leukemiaNucleic acid antisense oligonucleotideMinimal residual diseaseInhibition of survivinResidual diseaseSurvival advantageXenograft modelSurvivin expressionSurvivin inhibitionLeukemiaSurvivinChemotherapyRelapseAntisense oligonucleotideSurvivin/BIRC5Present studyApoptosis proteinInhibitionCellsPatientsBCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR–ABL1 kinase inhibition
Duy C, Hurtz C, Shojaee S, Cerchietti L, Geng H, Swaminathan S, Klemm L, Kweon SM, Nahar R, Braig M, Park E, Kim YM, Hofmann WK, Herzog S, Jumaa H, Koeffler HP, Yu JJ, Heisterkamp N, Graeber TG, Wu H, Ye BH, Melnick A, Müschen M. BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR–ABL1 kinase inhibition. Nature 2011, 473: 384-388. PMID: 21593872, PMCID: PMC3597744, DOI: 10.1038/nature09883.Peer-Reviewed Original ResearchMeSH KeywordsADP-Ribosylation Factor 1AnimalsCell SurvivalDNA-Binding ProteinsDrug Resistance, NeoplasmFusion Proteins, bcr-ablGene Expression Regulation, NeoplasticHumansMiceMice, Inbred NODMice, SCIDPrecursor Cell Lymphoblastic Leukemia-LymphomaProtein Kinase InhibitorsProto-Oncogene Proteins c-bcl-6Transcription, GeneticTumor Suppressor Protein p53ConceptsTyrosine kinase inhibitorsAcute lymphoblastic leukemia cellsBCR-ABL1 mutationsLymphoblastic leukemia cellsDrug resistanceLeukemia cellsLeukemia-initiating cellsXenograft modelBCR-ABL1Anticancer responseTargeted inhibitionDual inhibitionKinase inhibitorsOncogene withdrawalCancer therapyBCL6Kinase inhibitionLeukemiaInhibitionCellsTherapyMutationsUpregulation