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
Identification 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 promoter
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
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