2017
Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL
Schjerven H, Ayongaba EF, Aghajanirefah A, McLaughlin J, Cheng D, Geng H, Boyd JR, Eggesbø LM, Lindeman I, Heath JL, Park E, Witte ON, Smale ST, Frietze S, Müschen M. Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL. Journal Of Experimental Medicine 2017, 214: 793-814. PMID: 28190001, PMCID: PMC5339667, DOI: 10.1084/jem.20160049.Peer-Reviewed Original ResearchConceptsTumor suppressor functionHuman BCR-ABL1Target genesSuppressor functionDevelopmental stage-specific expressionGenome-wide chromatinStage-specific expressionWild-type IkarosTumor suppressor geneChromatin compactionIkaros functionGene pathwaysMultiple genesExpression analysisGenetic analysisInducible expressionTumor suppressorGenetic depletionCell surface markers CD34Suppressor geneGenesIkarosBCR-ABL1Cell acute lymphoblastic leukemiaLeukemic growth
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 Assays
2011
BCL6 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
2010
ABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1
Thai M, Ting P, McLaughlin J, Cheng D, Müschen M, Witte O, Colicelli J. ABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1. Leukemia 2010, 25: 290-300. PMID: 21102429, PMCID: PMC3049868, DOI: 10.1038/leu.2010.268.Peer-Reviewed Original ResearchConceptsBCR-ABL1Imatinib-resistant diseaseFirst-line therapyAcute lymphocytic leukemiaChronic myeloid leukemiaBCR-ABL1 kinase activityABL kinase inhibitor imatinibKinase inhibitor imatinibBCR-ABL1 activityBone marrow cellsAbl kinase inhibitorsDrug-resistant mutantsLeukemic casesMyeloid leukemiaLymphocytic leukemiaCell-autonomous mechanismsETV6-ABL1Inhibitor imatinibTyrosine kinase fusion proteinActive tyrosine kinaseMarrow cellsHematopoietic malignanciesKinase inhibitorsKinase fusion proteinGene translocationDevelopment of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia
Fei F, Stoddart S, Müschen M, Kim Y, Groffen J, Heisterkamp N. Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia. Leukemia 2010, 24: 813-820. PMID: 20111071, PMCID: PMC3038787, DOI: 10.1038/leu.2009.302.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBlotting, WesternCells, CulturedDasatinibDrug Resistance, NeoplasmEmbryo, MammalianFibroblastsFusion Proteins, bcr-ablHumansLeukemia, ExperimentalMiceMice, Inbred NODMice, KnockoutMice, SCIDPhosphorylationPrecursor Cell Lymphoblastic Leukemia-LymphomaProtein Kinase InhibitorsProtein-Tyrosine KinasesPyrimidinesReceptors, CXCR4Src-Family KinasesStromal CellsThiazolesConceptsLong-term treatmentBcr/Abl-positive acute lymphoblastic leukemiaPhiladelphia chromosome-positive leukemiaAcute lymphoblastic leukemia cellsLeukemia cellsTreatment of miceAcute lymphoblastic leukemiaEffects of dasatinibLymphoblastic leukemia cellsTyrosine kinase inhibitionDrug-resistant cellsHigh-dose pulseBCR/ABLDasatinib monotherapyDaily doseDevelopment of resistanceDasatinib treatmentLymphoblastic leukemiaB lineage cellsCell surface expressionCXCR4 inhibitorsEnhanced cell deathLow doseLow dosesDasatinib
2007
Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1–transformed acute lymphoblastic leukemia cells
Feldhahn N, Henke N, Melchior K, Duy C, Soh BN, Klein F, von Levetzow G, Giebel B, Li A, Hofmann WK, Jumaa H, Müschen M. Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1–transformed acute lymphoblastic leukemia cells. Journal Of Experimental Medicine 2007, 204: 1157-1166. PMID: 17485517, PMCID: PMC2118573, DOI: 10.1084/jem.20062662.Peer-Reviewed Original ResearchMeSH KeywordsB-LymphocytesBase SequenceBlotting, WesternCytidine DeaminaseDNA Mutational AnalysisDNA-Binding ProteinsFlow CytometryFusion Proteins, bcr-ablGene Expression Regulation, NeoplasticGenes, mycHumansImmunoglobulin Variable RegionMolecular Sequence DataMutationOligonucleotide Array Sequence AnalysisOligonucleotidesPhiladelphia ChromosomePrecursor Cell Lymphoblastic Leukemia-LymphomaProtein-Tyrosine KinasesProto-Oncogene Proteins c-bcl-6Reverse Transcriptase Polymerase Chain ReactionRNA InterferenceSequence AlignmentConceptsAcute lymphoblastic leukemiaBCR-ABL1BCR-ABL1 kinaseUnfavorable prognosisActivation-induced cytidine deaminaseAcute lymphoblastic leukemia cellsAID expressionAberrant AID expressionBCR-ABL1 kinase activityIgH V region genesTumor suppressor gene CDKN2BGerminal center B cellsLymphoblastic leukemia cellsB cell precursorsImmunoglobulin heavy chain variable region genesLymphoblastic leukemiaLeukemia subsetsB cellsDNA single-strand breaksPH casesPhiladelphia chromosomeHeavy chain variable region genesAberrant expressionCell precursorsChain variable region genes
2005
BCR–ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells
Klein F, Feldhahn N, Herzog S, Sprangers M, Mooster J, Jumaa H, Müschen M. BCR–ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells. Oncogene 2005, 25: 1118-1124. PMID: 16205638, DOI: 10.1038/sj.onc.1209133.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAnimalsAntineoplastic AgentsBenzamidesCell Line, TumorCell LineageCell NucleusFusion Proteins, bcr-ablGene Expression ProfilingGene SilencingHumansIkaros Transcription FactorImatinib MesylateMicePiperazinesPrecursor B-Cell Lymphoblastic Leukemia-LymphomaProtein Kinase InhibitorsProtein-Tyrosine KinasesPyrimidinesConceptsLymphoid lineage commitmentLineage commitmentGenome-wide gene expression profilesAberrant splicingLymphoblastic leukemia cellsLeukemia cellsAberrant expressionGene expression profilesNormal B-cell subsetsCell linesPrecursor cell lineLineage identityLineage infidelityTranscription factorsRNA interferenceExpression profilesInducible expressionUndifferentiated phenotypeSplice variantsDefective expressionBCR-ABL1SplicingIk6ExpressionCells
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