2020
Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia
Gang EJ, Kim HN, Hsieh YT, Ruan Y, Ogana HA, Lee S, Pham J, Geng H, Park E, Klemm L, Willman CL, Carroll WL, Mittelman SD, Orgel E, Oberley MJ, Parekh C, Abdel-Azim H, Bhojwani D, Wayne AS, De Arcangelis A, Georges-Labouesse E, Wayner E, Bonig H, Minasyan A, ten Hoeve J, Graeber TG, Müschen M, Heisterkamp N, Kim YM. Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia. Blood 2020, 136: 210-223. PMID: 32219444, PMCID: PMC7357190, DOI: 10.1182/blood.2019001417.Peer-Reviewed Original ResearchConceptsAcute lymphoblastic leukemiaDrug resistanceTyrosine kinase inhibitor treatmentIntegrin α6Minimal residual diseaseProteomic analysisAcute lymphoblastic B-cell leukemiaAdhesion-mediated drug resistanceKinase inhibitor treatmentNovel therapeutic targetConditional knockout modelCentral nervous systemSrc signalingB-cell leukemiaPhosphorylated LynCell adhesionVivo deletionKnockout modelsResidual diseaseLymphoblastic leukemiaKinase inhibitionTherapeutic targetNervous systemB cellsBCR-ABL1
2015
Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia
Shojaee S, Caeser R, Buchner M, Park E, Swaminathan S, Hurtz C, Geng H, Chan LN, Klemm L, Hofmann WK, Qiu YH, Zhang N, Coombes KR, Paietta E, Molkentin J, Koeffler HP, Willman CL, Hunger SP, Melnick A, Kornblau SM, Müschen M. Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia. Cancer Cell 2015, 28: 114-128. PMID: 26073130, PMCID: PMC4565502, DOI: 10.1016/j.ccell.2015.05.008.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Transformation, NeoplasticDNA-Binding ProteinsDual Specificity Phosphatase 6Host Cell Factor C1HumansIntracellular Signaling Peptides and ProteinsMAP Kinase Signaling SystemMembrane ProteinsMiceMice, TransgenicMolecular Sequence DataPrecursor Cell Lymphoblastic Leukemia-LymphomaPrognosisProtein Serine-Threonine KinasesSmall Molecule LibrariesTranscription FactorsConceptsAcute lymphoblastic leukemiaLymphoblastic leukemiaPatient-derived preNegative feedback regulationPre-B cell cloneCell deathImmediate cell deathMouse modelSmall molecule inhibitorsTherapeutic targetAcute activationMalignant transformationCell clonesFeedback regulationOncogenic signalingMolecule inhibitorsStrong activationLeukemiaDeathERKPre-B-cell transformationCell transformationActivationOncogenic transformationVast majorityMechanisms 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
Small-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 responsesC-terminalCatenin interactionSurvivin 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 proteinInhibitionCellsPatients
2010
Diet-Induced Obesity Accelerates Acute Lymphoblastic Leukemia Progression in Two Murine Models
Yun JP, Behan JW, Heisterkamp N, Butturini A, Klemm L, Ji L, Groffen J, Müschen M, Mittelman SD. Diet-Induced Obesity Accelerates Acute Lymphoblastic Leukemia Progression in Two Murine Models. Cancer Prevention Research 2010, 3: 1259-1264. PMID: 20823291, PMCID: PMC2955776, DOI: 10.1158/1940-6207.capr-10-0087.Peer-Reviewed Original ResearchConceptsAcute lymphoblastic leukemiaAKR miceLeukemia incidenceAKR/J miceOld obese miceSimilar median survivalEffect of obesityInterleukin-6 levelsObesity-related hormonesAcute lymphoblastic leukemia progressionDiet-Induced ObesityHigh-fat dietMedian survivalObese miceSpleen weightLymphoblastic leukemiaWBC countJ miceMurine modelObesityAnimal modelsLeukemia progressionLeukemia pathogenesisMiceObserved associations
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