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 efficacy
2018
Inhibition of PRMT1 Mediated FLT3 Arginine Methylation As a Potent Therapeutic Strategy for MLL-r ALL
Zhu Y, He X, Dong H, Sun J, Wang H, Zhang L, Miao Y, Jin J, Shen Y, Chen J, Muschen M, Chen C, Konopleva M, Sun W, Zhang B, Kuo Y, Carlesso N, Marcucci G, Li L. Inhibition of PRMT1 Mediated FLT3 Arginine Methylation As a Potent Therapeutic Strategy for MLL-r ALL. Blood 2018, 132: 892. DOI: 10.1182/blood-2018-99-115139.Peer-Reviewed Original Research
2016
Feedback Regulation of STAT5 Is Critical to Balance MYC and BCL6-Dependent Transcriptional Programs That Regulate Cell Size and Glucose Metabolism
Chen Z, Geng H, Klemm L, Chan L, Daniel B, Alexander W, Willman C, Müschen M. Feedback Regulation of STAT5 Is Critical to Balance MYC and BCL6-Dependent Transcriptional Programs That Regulate Cell Size and Glucose Metabolism. Blood 2016, 128: 4069. DOI: 10.1182/blood.v128.22.4069.4069.Peer-Reviewed Original ResearchBCR-ABL1Survival rateMedian expressionAdult B-lineageFree survival rateOverall survival rateWorse clinical outcomesGroup of patientsHigh expression levelsLeukemia cellsMRNA levelsNOD-SCID miceMYC expressionTyrosine kinase inhibitorsBCR-ABL1 tyrosine kinaseExpression levelsKinase inhibitory regionMedical Research CouncilAdvisory CommitteeInhibition of mTORGlucose consumptionCOG trialsLeukemia regressionTyrosine kinaseClinical outcomes
2015
Targeted Activation of B Cell Autoimmunity Checkpoints in Acute Lymphoblastic Leukemia
Chen Z, Geng H, Lowell C, Weiss A, Hunger S, Melnick A, Muschen M. Targeted Activation of B Cell Autoimmunity Checkpoints in Acute Lymphoblastic Leukemia. Blood 2015, 126: 3716. DOI: 10.1182/blood.v126.23.3716.3716.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsB cell receptorAcute lymphoblastic leukemiaPre-BCR signalingB cellsB cell selectionLymphoblastic leukemiaBCR-ABL1Autoreactive B cell receptorsCell deathPre-B-cell originAcute lymphoblastic leukemia cellsCurrent therapy approachesLeukemia cellsWorse clinical outcomesSelf-reactive B cellsNegative B cell selectionPotent tyrosine kinase inhibitorLymphoblastic leukemia cellsNovel small molecule inhibitorTypes of cancerUbiquitous self-antigenClinical outcomesIncremental increasePoor outcomeTargeting of Quiescent and Proliferating CML Stem Cells By DNA Repair Inhibitors
Sullivan K, Bolton-Gillespie E, Nieborowska-Skorska M, Cerny-Reiterer S, Valent P, Muschen M, Pomerantz R, Mazin A, Skorski T. Targeting of Quiescent and Proliferating CML Stem Cells By DNA Repair Inhibitors. Blood 2015, 126: 50. DOI: 10.1182/blood.v126.23.50.50.Peer-Reviewed Original ResearchQuiescent leukemia stem cellsLeukemia stem cellsTyrosine kinase inhibitorsChronic myeloid leukemiaCML cellsBCR-ABL1Myeloid leukemiaAnti-leukemia effectSimultaneous targetingCML leukemia stem cellsNew treatment modalitiesPARP1 inhibitorsCML stem cellsNormal counterpartsDouble knockout miceAdditional chromosomal aberrationsTKI-resistant BCRStem cellsBristol-Myers SquibbTKI therapyDisease relapseChronic phaseGood respondersCML patientsTreatment modalitiesOvercoming 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 miceSelf-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia
Geng H, Hurtz C, Lenz KB, Chen Z, Baumjohann D, Thompson S, Goloviznina NA, Chen WY, Huan J, LaTocha D, Ballabio E, Xiao G, Lee JW, Deucher A, Qi Z, Park E, Huang C, Nahar R, Kweon SM, Shojaee S, Chan LN, Yu J, Kornblau SM, Bijl JJ, Ye BH, Ansel KM, Paietta E, Melnick A, Hunger SP, Kurre P, Tyner JW, Loh ML, Roeder RG, Druker BJ, Burger JA, Milne TA, Chang BH, Müschen M. Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia. Cancer Cell 2015, 27: 409-425. PMID: 25759025, PMCID: PMC4618684, DOI: 10.1016/j.ccell.2015.02.003.Peer-Reviewed Original ResearchMeSH KeywordsBasic Helix-Loop-Helix Transcription FactorsClinical Trials as TopicDNA-Binding ProteinsGene Expression Regulation, NeoplasticHumansIntracellular Signaling Peptides and ProteinsMolecular Sequence DataPhosphatidylinositol 3-KinasePre-B-Cell Leukemia Transcription Factor 1Precursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidProtein-Tyrosine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-6Signal TransductionSrc-Family KinasesSyk KinaseUp-RegulationConceptsDistinct subtypesPre-BCR signalingPatient-derived preVivo treatment studiesTreatment of patientsAcute lymphoblastic leukemiaTyrosine kinase inhibitorsPre-B cell receptor signalingCell receptor signalingLymphoblastic leukemiaClinical trialsTreatment studiesPre-BCR functionReceptor signalingKinase inhibitorsDistinct subsetsBCL6 expressionInduced activationFeedback activationSubtypesTyrosine kinaseBCL6SignalingActivationTranscriptional level
2014
Harnessing Negative B Cell Selection to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia
Chen Z, Shojaee S, Geng H, Lee J, Buchner M, Klemm L, Lowell C, Paietta E, Willman C, Carroll W, Melnick A, Jung J, Jumaa H, Coligan J, Bolland S, Mak T, Muschen M. Harnessing Negative B Cell Selection to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia. Blood 2014, 124: 792. DOI: 10.1182/blood.v124.21.792.792.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaTyrosine kinase inhibitorsB cell receptorInhibitory receptorsTherapeutic targetPre-BCR signalingLymphoblastic leukemiaXenograft cellsB cellsSurvival rateB-cell acute lymphoblastic leukemiaCell deathAuto-reactive clonesFree survival rateCell acute lymphoblastic leukemiaOverall survival rateWorse clinical outcomesLeukemia cellsNegative B cell selectionAdditional therapeutic targetsAvailable therapeutic interventionsG1cell cycle arrestPotent tyrosine kinase inhibitorNovel small molecule inhibitorColony formation capacityThe Linker Protein GAS7 Negatively Regulates Pre-B Cell Differentiation and Amplifies Proliferation and Survival Signals in Acute Lymphoblastic Leukemia
Lee J, Buchner M, Geng H, Swaminathan S, Park E, Park A, Lin-Chao S, So C, Muschen M. The Linker Protein GAS7 Negatively Regulates Pre-B Cell Differentiation and Amplifies Proliferation and Survival Signals in Acute Lymphoblastic Leukemia. Blood 2014, 124: 3777. DOI: 10.1182/blood.v124.21.3777.3777.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaTyrosine kinase inhibitorsLymphoblastic leukemiaBCR-ABL1B-cell lineage leukemiaPre-B cell differentiationTyrosine kinase inhibitor treatmentPediatric acute lymphoblastic leukemiaTreatment-related acute myeloid leukemiaAcute myeloid leukemiaPre-B cell receptor checkpointKinase inhibitor treatmentEffects of Stat5Spontaneous IgNormal B cell developmentMyeloid leukemiaB cell progenitorsBone marrowCell differentiationInhibitor treatmentB cell developmentLeukemiaSelf-renewal capacityConditional deletionKinase inhibitors
2013
Identification Of FOXM1 As Therapeutic Target In BCR-ABL1 Positive Acute Lymphoblastic Leukemia
Buchner M, Park E, Klemm L, Geng H, Kopanja D, Raychaudhuri P, Muschen M. Identification Of FOXM1 As Therapeutic Target In BCR-ABL1 Positive Acute Lymphoblastic Leukemia. Blood 2013, 122: 1250. DOI: 10.1182/blood.v122.21.1250.1250.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsAcute lymphoblastic leukemiaPositive acute lymphoblastic leukemiaPoor clinical outcomeFoxM1 expression levelBCR-ABL1Clinical outcomesB cell precursorsImatinib treatmentLymphoblastic leukemiaDisease progressionBreakpoint cluster regionTherapeutic targetBCR-ABL1 tyrosine kinase activityCatalase expressionPhiladelphia chromosome-positive acute lymphoblastic leukemiaSmall molecule tyrosine kinase inhibitorsFoxm1 deletionExpression levelsMolecule tyrosine kinase inhibitorsCell precursorsDeletion of Foxm1Münster Study GroupGood clinical responseIntracellular reactive oxygen species (ROS) formationGas7 Induces The Proliferation Of Ph+ ALL Cells and Prevents The Differentiation Of Early B Cell Progenitors Into CD25high Small Pre-B Cells
Lee J, Buchner M, Geng H, Swaminathan S, Park E, Klemm L, Lin-Chao S, So C, Muschen M. Gas7 Induces The Proliferation Of Ph+ ALL Cells and Prevents The Differentiation Of Early B Cell Progenitors Into CD25high Small Pre-B Cells. Blood 2013, 122: 2506. DOI: 10.1182/blood.v122.21.2506.2506.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaAcute myeloid leukemiaTyrosine kinase inhibitorsB cell progenitorsBCR-ABL1B cell developmentEarly B cell developmentCell progenitorsB-cell lineage leukemiaPediatric acute lymphoblastic leukemiaMotor neuron numberBone marrow B-cell progenitorsEffects of Stat5Growth arrest-specific gene 7Levels of p21Leukemia cell survivalExpression of intracellularLymphoblastic leukemiaIL7R expressionMyeloid leukemiaBone marrowB cellsInterleukin-7Pre B cellsSelf-renewal capacityInhibitory Receptors and Phosphatases Enable Oncogenic Tyrosine Kinase Signaling In B Cell Lineage Leukemia
Chen Z, Shojaee S, Geng H, Lee J, Buchner M, Klemm L, Lowell C, Paietta E, Willman C, Carroll W, Melnick A, Jung J, Jumaa H, Coligan J, Bolland S, Mak T, Muschen M. Inhibitory Receptors and Phosphatases Enable Oncogenic Tyrosine Kinase Signaling In B Cell Lineage Leukemia. Blood 2013, 122: 229. DOI: 10.1182/blood.v122.21.229.229.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaB cell receptorTyrosine kinase inhibitorsInhibitory receptorsTherapeutic targetB cellsBCR-ABL1Survival rateB-cell lineage leukemiaCell deathAuto-reactive clonesFree survival rateLeukemia cellsOverall survival rateWorse clinical outcomesG0/G1 cell cycle arrestAdditional therapeutic targetsCycle arrestAvailable therapeutic interventionsG1cell cycle arrestPotential therapeutic targetG1 cell cycle arrestOncogenic tyrosine kinasesNovel small molecule inhibitorCellular senescenceTargeting Pre-B Cell Receptor and BCL6 In TCF3-PBX1 B-Lineage Acute Lymphoblastic Leukemia
Geng H, Hurtz C, Chen Z, Chen W, Ballabio E, Xiao G, Kweon S, Nahar R, Sojaee S, Chan L, Masouleh B, Sykes D, Melnick A, Roeder R, Milne T, Muschen M. Targeting Pre-B Cell Receptor and BCL6 In TCF3-PBX1 B-Lineage Acute Lymphoblastic Leukemia. Blood 2013, 122: 349. DOI: 10.1182/blood.v122.21.349.349.Peer-Reviewed Original ResearchPre-BCR signalingGene expression microarray dataB-lineage acute lymphoblastic leukemiaExpression microarray dataTyrosine kinase inhibitorsPre-B cell receptorCell deathMicroarray dataPre-BCR componentsPoor clinical outcomeAcute lymphoblastic leukemiaTCF3-PBX1Cell line 697Cell cycle arrestTranscriptional repressor BCL6ChIPseq dataPre-BCRChIP-seqCellular processesClinical outcomesCritical survival factorTherapeutic targetLeukemia cellsLymphoblastic leukemiaTransplant recipient mice
2012
BACH2 Is Required for Pre-B Cell Receptor Checkpoint Control and p53-Dependent Tumor Surveillance
Swaminathan S, Kang H, Harvey R, Huang C, Buchner M, Chen Z, Geng H, Hall A, Igarashi K, Carroll W, Willman C, Melnick A, Muschen M. BACH2 Is Required for Pre-B Cell Receptor Checkpoint Control and p53-Dependent Tumor Surveillance. Blood 2012, 120: 1300. DOI: 10.1182/blood.v120.21.1300.1300.Peer-Reviewed Original ResearchFavorable clinical outcomeTyrosine kinase inhibitorsPre-B cell cloneOncogene-induced senescenceClinical outcomesLeukemia cellsB cellsBCR-ABL1Multivariate analysisCell clonesAcute lymphoblastic leukemia cellsTime of diagnosisMRNA levelsTumor suppressor CDKN2AGerminal center B cellsLymphoblastic leukemia cellsEvidence of MRDNormal human bone marrowCases of childhoodSigns of diseaseRelapse of childhoodBACH2 locusImmunoglobulin heavy chain geneQuantitative RT-PCRMYC resultsFunctional 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
Targeting Inhibitory Phosphatases in Tyrosine Kinase-Driven Leukemias
Shojaee S, Buchner M, Geng H, Silvia B, Koeffler P, Muschen M. Targeting Inhibitory Phosphatases in Tyrosine Kinase-Driven Leukemias. Blood 2011, 118: 1382. DOI: 10.1182/blood.v118.21.1382.1382.Peer-Reviewed Original ResearchCell deathReactive oxygen speciesInducible deletionLeukemia cellsTyrosine kinase signalingActivation signalsSmall molecule inhibitionSubsequent cell deathMultiple new targetsLeukemia cell deathBCR-ABL1 oncogeneCytoplasmic tailKinase signalingTransplant recipient miceInduction of CreTyrosine kinase inhibitorsCellular senescenceMolecule inhibitionTyrosine kinasePTPN6Drastic upregulationINPP5DCurrent tyrosine kinase inhibitorsPTENDeletionBCL6-Mediated Repression of p53 Is Critical for Leukemia Stem Cell Survival in Chronic Myeloid Leukemia
Hurtz C, Hatzi K, Cerchietti L, Park E, Kim Y, Ramezani-Rad P, Jumaa H, Muller M, Hofmann W, Hochhaus A, Agarwal A, Shah N, Melnick A, Druker B, Muschen M. BCL6-Mediated Repression of p53 Is Critical for Leukemia Stem Cell Survival in Chronic Myeloid Leukemia. Blood 2011, 118: 446. DOI: 10.1182/blood.v118.21.446.446.Peer-Reviewed Original ResearchBACH2 Mediates Early B Cell Differentiation and Oncogene-Induced Senescence in Acute Lymphoblastic Leukemia
Swaminathan S, Huang C, Titz B, Buchner M, Geng H, Graeber T, Willman C, Igarashi K, Melnick A, Muschen M. BACH2 Mediates Early B Cell Differentiation and Oncogene-Induced Senescence in Acute Lymphoblastic Leukemia. Blood 2011, 118: 562. DOI: 10.1182/blood.v118.21.562.562.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsRelapse of childhoodBCR-ABL1B cell differentiationDay 29Leukemia cellsB cellsMRNA levelsOverexpression of MYCEarly B cell differentiationAcute lymphoblastic leukemia cellsAcute lymphoblastic leukemiaTumor suppressor CDKN2AGerminal center B cellsLymphoblastic leukemia cellsEvidence of MRDNormal human bone marrowSigns of diseaseCommon gene expression signatureFraction of casesPositive MRDQuantitative RT-PCRRole of Bach2Gene expression signaturesImatinib treatmentBCL6-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