2019
Rationale for targeting BCL6 in MLL-rearranged acute lymphoblastic leukemia
Hurtz C, Chan LN, Geng H, Ballabio E, Xiao G, Deb G, Khoury H, Chen CW, Armstrong SA, Chen J, Ernst P, Melnick A, Milne T, Müschen M. Rationale for targeting BCL6 in MLL-rearranged acute lymphoblastic leukemia. Genes & Development 2019, 33: 1265-1279. PMID: 31395741, PMCID: PMC6719625, DOI: 10.1101/gad.327593.119.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiomarkers, TumorCell SurvivalCells, CulturedGene DeletionGene Expression Regulation, LeukemicGene TargetingHumansMiceMyeloid-Lymphoid Leukemia ProteinOncogene Proteins, FusionPrecursor Cell Lymphoblastic Leukemia-LymphomaPrognosisPromoter Regions, GeneticProto-Oncogene Proteins c-bcl-6ConceptsB-cell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaLymphoblastic leukemiaPharmacological inhibitionGroup of patientsBCL6 expressionBone marrow biopsyBH3 mimetic ABT-199Transplant recipient miceMLL fusionsB-cell transformationMarrow biopsyTreatment of MLLDismal outcomeRecipient miceNormal B cell developmentImmunohistochemical stainingTranscriptional activationB cell developmentMalignant transformationDrug resistanceGenetic deletionPatient samplesExpression of BimMLL-ENL fusion
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
2017
Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia
Takao S, Chien W, Madan V, Lin D, Ding L, Sun Q, Mayakonda A, Sudo M, Xu L, Chen Y, Jiang Y, Gery S, Lill M, Park E, Senapedis W, Baloglu E, Müschen M, Koeffler H. Targeting the vulnerability to NAD+ depletion in B-cell acute lymphoblastic leukemia. Leukemia 2017, 32: 616-625. PMID: 28904384, DOI: 10.1038/leu.2017.281.Peer-Reviewed Original ResearchMeSH KeywordsAcrylamidesAminopyridinesAnimalsAntineoplastic AgentsApoptosisCell Line, TumorCell ProliferationCell SurvivalCytokinesDisease Models, AnimalFemaleHumansMaleMiceNADNicotinamide PhosphoribosyltransferaseP21-Activated KinasesPrecursor B-Cell Lymphoblastic Leukemia-LymphomaSignal TransductionXenograft Model Antitumor AssaysConceptsB-cell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaP21-activated kinase 4Nicotinamide phosphoribosyltransferaseLymphoblastic leukemiaNAMPT inhibitionPatient-derived xenograft murine modelsPrognosis of patientsNicotinamide adenine dinucleotideNovel therapeutic strategiesNicotinic acid supplementationNovel dual inhibitorXenograft murine modelCell growth inhibitionAcid supplementationMurine modelTherapeutic strategiesRate-limiting enzymeCytogenetic abnormalitiesVivo efficacyPatientsNAMPT inhibitorsInhibitory effectDual inhibitorKinase 4
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
BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint
Swaminathan S, Huang C, Geng H, Chen Z, Harvey R, Kang H, Ng C, Titz B, Hurtz C, Sadiyah MF, Nowak D, Thoennissen GB, Rand V, Graeber TG, Koeffler HP, Carroll WL, Willman CL, Hall AG, Igarashi K, Melnick A, Müschen M. BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. Nature Medicine 2013, 19: 1014-1022. PMID: 23852341, PMCID: PMC3954721, DOI: 10.1038/nm.3247.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBasic-Leucine Zipper Transcription FactorsCell DeathCell DifferentiationCell SurvivalCell Transformation, NeoplasticDNA-Binding ProteinsGene DeletionGene Expression Regulation, LeukemicGreen Fluorescent ProteinsImmunoglobulin mu-ChainsMiceMolecular Sequence DataPAX5 Transcription FactorPre-B Cell ReceptorsPrecursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidProto-Oncogene Proteins c-bcl-6Proto-Oncogene Proteins c-mycRNA, MessengerSTAT5 Transcription FactorTreatment OutcomeTumor Suppressor Protein p53V(D)J Recombination
2011
BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia
Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM, Herzog S, Ramezani-Rad P, Jumaa H, Müller MC, Hofmann WK, Hochhaus A, Ye BH, Agarwal A, Druker BJ, Shah NP, Melnick AM, Müschen M. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. Journal Of Experimental Medicine 2011, 208: 2163-2174. PMID: 21911423, PMCID: PMC3201200, DOI: 10.1084/jem.20110304.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CD34BenzamidesCell SurvivalDisease Models, AnimalDNA-Binding ProteinsForkhead Transcription FactorsHematopoietic Stem CellsHumansImatinib MesylateLeukemia, Myelogenous, Chronic, BCR-ABL PositiveMiceMice, Inbred NODMice, KnockoutMice, SCIDNeoplasm TransplantationNeoplastic Stem CellsPiperazinesProtein Kinase InhibitorsProtein-Tyrosine KinasesProto-Oncogene Proteins c-bcl-6PyrimidinesTumor Cells, CulturedTumor Suppressor Protein p53ConceptsChronic myeloid leukemiaLeukemia-initiating cellsCML-initiating cellsTyrosine kinase inhibitorsTKI treatmentCML patientsMyeloid leukemiaCML cellsInhibition of BCL6Leukemia stem cell survivalLeukemia initiationHuman CML cellsColony formationBCR-ABL1 tyrosine kinaseInitiation of leukemiaTransplant recipientsBlast crisis transformationRepression of p53Pharmacological inhibitionStem cell survivalCML samplesLeukemiaClinical validationKinase inhibitorsBCL6BCL6 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
2005
Mimicry of a constitutively active pre–B cell receptor in acute lymphoblastic leukemia cells
Feldhahn N, Klein F, Mooster JL, Hadweh P, Sprangers M, Wartenberg M, Bekhite MM, Hofmann WK, Herzog S, Jumaa H, Rowley JD, Müschen M. Mimicry of a constitutively active pre–B cell receptor in acute lymphoblastic leukemia cells. Journal Of Experimental Medicine 2005, 201: 1837-1852. PMID: 15939795, PMCID: PMC2213268, DOI: 10.1084/jem.20042101.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedCalcium SignalingCell Line, TumorCell SurvivalChildChild, PreschoolFemaleGene Expression Regulation, LeukemicHumansMaleMembrane GlycoproteinsMiddle AgedMolecular MimicryPre-B Cell ReceptorsPrecursor Cell Lymphoblastic Leukemia-LymphomaProtein-Tyrosine KinasesReceptors, Antigen, B-CellConceptsBruton's tyrosine kinaseBCR-ABL1Pre-B cell receptorCell receptorFull‐length Bruton tyrosine kinaseSurvival signalsAcute lymphoblastic leukemia cellsLeukemia cellsBCR-ABL1 kinase activityLymphoblastic leukemia cellsDownstream survival signalsBCR-ABL1 kinaseTyrosine kinaseCell receptor engagementKinase activityBypass selectionSTAT5 phosphorylationSrc homology domain 3BTK activityReceptorsAutonomous Ca2Receptor engagementSimilar extentActivation of PLCgamma1Dependent activation
1999
Involvement of Soluble CD95 in Churg-Strauss Syndrome
Müschen M, Warskulat U, Perniok A, Even J, Moers C, Kismet B, Temizkan N, Simon D, Schneider M, Häussinger D. Involvement of Soluble CD95 in Churg-Strauss Syndrome. American Journal Of Pathology 1999, 155: 915-925. PMID: 10487849, PMCID: PMC1866905, DOI: 10.1016/s0002-9440(10)65191-7.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedApoptosisCell SurvivalCells, CulturedChurg-Strauss SyndromeClone CellsCulture Media, ConditionedEnzyme-Linked Immunosorbent AssayEosinophilsFas Ligand ProteinFas ReceptorFemaleGenes, T-Cell Receptor betaHumansImmunosuppressive AgentsMaleMembrane GlycoproteinsMiddle AgedMultigene FamilyReceptors, Tumor Necrosis FactorReverse Transcriptase Polymerase Chain ReactionRNA, MessengerT-LymphocytesConceptsChurg-Strauss syndromeSoluble CD95CSS patientsOligoclonal T cell expansionTCR Vbeta gene usageAutoimmune lymphoproliferative disordersVbeta gene usageRole of eosinophilsT cell expansionPeripheral blood lymphocytesT cell clonesSoluble splice variantCD95L-mediated apoptosisCD95 receptor expressionImmunosuppressive therapyClinical improvementCDR3 motifsEffector cellsLymphoproliferative disordersCS patientsBlood lymphocytesReceptor expressionHealthy individualsVbeta genesEosinophils