2019
Effective Novel Fto Inhibitors Show Potent Anti-Cancer Efficacy and Suppress Drug Resistance
Su R, Dong L, Li Y, Han L, Gao M, Wunderlich M, Deng X, Li H, Gao L, Li C, Robison S, Tan B, Qing Y, Qin X, Prince E, Xie J, Qin H, Huang Y, Li W, Shen C, Sun J, Prakash K, Weng H, Huang H, Chen Z, Zhang B, Wu X, Olsen M, Müschen M, Marcucci G, Ravi S, Li L, Yang C, Li Z, Mulloy J, Wei M, Horne D, Chen J. Effective Novel Fto Inhibitors Show Potent Anti-Cancer Efficacy and Suppress Drug Resistance. Blood 2019, 134: 233. DOI: 10.1182/blood-2019-124535.Peer-Reviewed Original ResearchAML cell linesAnti-leukemic effectsAML cellsMouse modelDrug resistanceAcute myeloid leukemia patientsPotent anti-leukemic effectCell linesPotent anti-cancer efficacyAML cell viabilitySuppress drug resistanceAML mouse modelAnti-leukemia effectMyeloid leukemia patientsAnti-leukemic efficacyTransplantation mouse modelMurine AML cellsOnset of leukemiaFTO inhibitorsPotent therapeutic efficacyTyrosine kinase inhibitorsXenograft mouse modelAnti-leukemic activityFTO proteinAnti-AML efficacyRationale 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
Autoimmunity checkpoints as therapeutic targets in B cell malignancies
Müschen M. Autoimmunity checkpoints as therapeutic targets in B cell malignancies. Nature Reviews Cancer 2018, 18: 103-116. PMID: 29302068, DOI: 10.1038/nrc.2017.111.Peer-Reviewed Original Research
2015
Overcoming Drug Resistance of Pre-B ALL Cells By Targeting Integrin alpha6 Associated Cell-Adhesion Mediated Drug Resistance Using a Novel Antibody, P5G10
Gang E, Hsieh Y, Kim H, Duchartre Y, Stephanie S, Muschen M, Wayner E, Heisterkamp N, Bonig H, Kim Y. Overcoming Drug Resistance of Pre-B ALL Cells By Targeting Integrin alpha6 Associated Cell-Adhesion Mediated Drug Resistance Using a Novel Antibody, P5G10. Blood 2015, 126: 2525. DOI: 10.1182/blood.v126.23.2525.2525.Peer-Reviewed Original ResearchMinimal residual diseaseTyrosine kinase inhibitorsPeripheral bloodDrug resistanceFlow cytometryLeukemia cellsRecipient miceHuman CD45Bone marrowBCR-ABL1NOD/SCID miceControl recipient miceCell adhesion-mediated drug resistanceAdhesion-mediated drug resistanceNovel therapeutic targetControl-treated cellsCell-bearing miceChemotherapy-resistant cellsPercentage of adherenceLaminin-1Integrin alpha 6Mesenchymal stromal cellsNormal hematopoietic cellsOvercoming Drug ResistanceUntreated miceSignalling 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
2012
Functional Modulation of VLA6 in BCR-ABL1+ Pre-B Acute Lymphoblastic Leukemia.
Gang E, Hsieh Y, Geng H, Pham J, Muschen M, de Arcangelis A, Willman C, Carroll W, Georges-Labouesse E, Bonig H, Kim Y. Functional Modulation of VLA6 in BCR-ABL1+ Pre-B Acute Lymphoblastic Leukemia. Blood 2012, 120: 2565. DOI: 10.1182/blood.v120.21.2565.2565.Peer-Reviewed Original ResearchMedian survival timeAcute lymphoblastic leukemiaBCR/ABL1Tyrosine kinase inhibitorsBCR-ABL1Leukemia progressionDrug resistanceBone marrow environmentLeukemia cellsLymphoblastic leukemiaPre-B Acute Lymphoblastic LeukemiaFlow cytometryNOD/SCID micePoor clinical outcomeCell adhesion-mediated drug resistanceChronic myeloid leukemiaMinimal residual diseaseChemotherapy drug resistanceAdhesion-mediated drug resistanceAddition of tamoxifenNormal B cellsModels of leukemiaVivo deletionConditional knockout modelNilotinib treatment
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
WNT/β-Catenin Signaling in Leukemia
Müschen M. WNT/β-Catenin Signaling in Leukemia. 2010, 129-142. DOI: 10.1007/978-1-4419-8023-6_6.Peer-Reviewed Original ResearchWnt/β-catenin signalingΒ-catenin signalingLeukemia stem cellsLeukemia-initiating cellsStem cellsRelapse of leukemiaMajor clinical problemWnt/β-cateninNovel therapy approachesActive Wnt/β-catenin signalingNormal hematopoiesisTreatment of leukemiaLeukemic cloneClinical problemLeukemia subtypesLeukemiaHematopoietic stem cellsNatural historyDrug resistanceMalignant outgrowthMultiple hematopoietic lineagesProgenitor cellsΒ-cateninTherapy approachesMyeloid progenitorsAdjuvant CD49d Blockade Eradicates Chemoresistant ALL
Hsieh Y, Park E, Jiang E, Dauber K, Chudziak D, Schaefer P, Klemm L, Scharman C, Kang E, Koo H, Loh M, Hofmann W, Heisterkamp N, Muschen M, Shimada H, Bonig H, Kim Y. Adjuvant CD49d Blockade Eradicates Chemoresistant ALL. Blood 2010, 116: 869. DOI: 10.1182/blood.v116.21.869.869.Peer-Reviewed Original ResearchAcute lymphocytic leukemiaNOD/SCID miceBone marrow cellsSCID miceSurvival timeB-lineage acute lymphocytic leukemiaCounter-receptor VCAM-1Drug resistanceNOD/SCID xenograft modelLong-term side effectsMarrow cellsChemotherapy-resistant leukemiaDose-limiting toxicityLeukemia cellsSaline-treated groupCell adhesion-mediated drug resistanceMedian survival timeImmunocompetent mouse modelRelapse of leukemiaSCID xenograft modelAcute lymphoblastic leukemiaMurine leukemiaProlonged survival timeNew treatment modalitiesAdhesion-mediated drug resistance
2009
Targeting Survivin Using ICG-001 May Overcome Drug Resistance in Primary B-Cell Acute Lymphoblastic Leukemia.
Jiang E, Park E, Scharman C, Hsieh Y, Kadavallore A, Nguyen C, Zhao Y, McMillan M, Groffen J, Heisterkamp N, Muschen M, Kahn M, Kim Y. Targeting Survivin Using ICG-001 May Overcome Drug Resistance in Primary B-Cell Acute Lymphoblastic Leukemia. Blood 2009, 114: 3072. DOI: 10.1182/blood.v114.22.3072.3072.Peer-Reviewed Original ResearchMedian survival timeAcute lymphoblastic leukemiaWhite blood cellsICG-001Control groupBlood cellsStandard chemotherapyRed blood cellsPeripheral bloodLymphoblastic leukemiaSmall molecule inhibitor ICG-001B-cell acute lymphoblastic leukemiaDrug resistanceCBP/β-cateninNormal hematopoiesisPromising therapeutic principleNormal white blood cellsConventional drug treatmentLeukemia cellsPrior intravenous injectionEnd of treatmentNovel therapeutic optionsNormal weight gainNew treatment modalitiesSubcutaneous osmotic pumpsThe B Cell Mutator AID Promotes B Lymphoid Blast Crisis and Drug-Resistance in Chronic Myeloid Leukemia.
Klemm L, Duy C, Iacobucci I, von Levetzow G, Feldhahn N, Kim Y, Hofmann W, Jumaa H, Groffen J, Heisterkamp N, Martinelli G, Lieber M, Casellas R, Müschen M. The B Cell Mutator AID Promotes B Lymphoid Blast Crisis and Drug-Resistance in Chronic Myeloid Leukemia. Blood 2009, 114: 3274. DOI: 10.1182/blood.v114.22.3274.3274.Peer-Reviewed Original ResearchBCR-ABL1 mutationsChronic myeloid leukemiaLymphoid blast crisisB-lymphoid blast crisisBCR-ABL1 kinase domainImatinib resistanceCML cellsBCR-ABL1Gene copy number alterationsDrug resistanceLeukemia cellsOverall survivalMyeloid leukemiaBlast crisisFive-year overall survivalCopy number alterationsNOD/SCID miceMedian overall survivalTreatment of patientsExpression of CD19Imatinib-resistant clonesMechanisms of progressionKinase inhibitor imatinibPresence of imatinibConcentrations of imatinib