2023
Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia
Chen Z, Zhou K, Xue J, Small A, Xiao G, Nguyen L, Zhang Z, Prince E, Weng H, Huang H, Zhao Z, Qing Y, Shen C, Li W, Han L, Tan B, Su R, Qin H, Li Y, Wu D, Gu Z, Ngo V, He X, Chao J, Leung K, Wang K, Dong L, Qin X, Cai Z, Sheng Y, Chen Y, Wu X, Zhang B, Shi Y, Marcucci G, Qian Z, Xu M, Müschen M, Chen J, Deng X. Phosphorylation stabilized TET1 acts as an oncoprotein and therapeutic target in B cell acute lymphoblastic leukemia. Science Translational Medicine 2023, 15: eabq8513. PMID: 36989375, PMCID: PMC11163962, DOI: 10.1126/scitranslmed.abq8513.Peer-Reviewed Original ResearchConceptsB-cell acute lymphoblastic leukemiaCell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaB-ALLRefractory/Oncogenic roleLymphoblastic leukemiaProtein kinase C epsilonOverall survival rateNormal precursor B cellsCrucial oncogenic rolePrecursor B cellsAdult patientsPDX modelsPharmacological targetingTherapeutic targetB cellsImproved therapiesSurvival rateLeukemia progressionTherapeutic potentialOverexpression of TET1TET1 proteinATM serine/threonine kinaseLeukemia
2022
Phosphorylation Stabilized TET1 Acts As an Oncoprotein and Therapeutic Target in B-Cell Acute Lymphoblastic Leukemia
Chen Z, Zhou K, Xue J, Small A, Xiao G, Nguyen L, Zhang Z, Prince E, Weng H, Huang H, Zhao Z, Qing Y, Shen C, Han L, Tan B, Li W, Su R, Qin H, Li Y, Wu D, Gu Z, Ngo V, He X, Chao J, Leung K, Wang K, Dong L, Qin X, Cai Z, Sheng Y, Chen Y, Wu X, Zhang B, Shi Y, Marcucci G, Qian Z, Xu M, Müschen M, Deng X, Chen J. Phosphorylation Stabilized TET1 Acts As an Oncoprotein and Therapeutic Target in B-Cell Acute Lymphoblastic Leukemia. Blood 2022, 140: 998-1000. DOI: 10.1182/blood-2022-165469.Peer-Reviewed Original Research
2021
Protein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer
Mirzapoiazova T, Xiao G, Mambetsariev B, Nasser MW, Miaou E, Singhal SS, Srivastava S, Mambetsariev I, Nelson MS, Nam A, Behal A, Arvanitis LD, Atri P, Muschen M, Tissot FLH, Miser J, Kovach JS, Sattler M, Batra SK, Kulkarni P, Salgia R. Protein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer. Molecular Cancer Therapeutics 2021, 20: 1820-1835. PMID: 34253596, PMCID: PMC8722383, DOI: 10.1158/1535-7163.mct-21-0013.Peer-Reviewed Original ResearchConceptsProtein phosphatase 2APhosphatase 2ASerine/threonine phosphataseDNA damage responseRegulation of apoptosisSmall molecule inhibitorsGlycolytic ATP productionThreonine phosphataseTwo-dimensional cultureLB100ATP productionMolecule inhibitorsPP2AThree-dimensional spheroid modelEndothelial cell monolayersGlucose uptakeCell viabilitySCLC cellsTherapeutic targetApoptosisCell monolayersMass spectrometrySpheroid modelTumor spheroidsCells
2019
Identification of ZNF217 As an Essential Oncogenic Gene in B-Cell Acute Lymphoblastic Leukemia By CRISPR/Cas9-Based Library Screening
Qin X, Su R, Yang L, Chan A, Deng X, Qing Y, Klemm L, Müschen M, Chen C, Chen J. Identification of ZNF217 As an Essential Oncogenic Gene in B-Cell Acute Lymphoblastic Leukemia By CRISPR/Cas9-Based Library Screening. Blood 2019, 134: 1465. DOI: 10.1182/blood-2019-129849.Peer-Reviewed Original ResearchB-cell acute lymphoblastic leukemiaBCR-ABL1 fusionAcute lymphoblastic leukemiaAcute myeloid leukemiaAML cellsM6A regulatorsMLL-AF4 fusionAdult patientsLymphoblastic leukemiaPediatric B-cell acute lymphoblastic leukemiaEssential oncogenic roleM6A modificationMessenger RNACytogenetic characteristicsDismal survivalMyeloid leukemiaB cell progenitorsTherapeutic targetOncogenic roleSolid tumorsPatientsZinc finger protein 217B-lineageLeukemiaCytogenetic changes
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
2016
Identification of the Energy Stress Sensor AMPK As Therapeutic Target in Acute Lymphoblastic Leukemia
Chan L, Lee J, Cosgun K, Geng H, Xiao G, Chen Z, Ernst T, Hochhaus A, Müschen M. Identification of the Energy Stress Sensor AMPK As Therapeutic Target in Acute Lymphoblastic Leukemia. Blood 2016, 128: 2771. DOI: 10.1182/blood.v128.22.2771.2771.Peer-Reviewed Original ResearchChronic myeloid leukemiaAcute lymphoblastic leukemiaMyeloid leukemiaTransplant recipient miceB-cell lineageLKB1/AMPKLymphoblastic leukemiaRecipient miceCML cellsTherapeutic targetLong-term disease-free survivalPhiladelphia chromosome-positive acute lymphoblastic leukemiaB-cell lineage leukemiaPatient-derived preDisease-free survivalInducible deletionNovel therapeutic targetGlycolytic activityBCR-ABL1 tyrosine kinaseNovel therapeutic avenuesATP levelsMitochondrial functionCell deathInitial remissionClinical characteristicsCD25 Enables Oncogenic BCR Signaling and Represents a Therapeutic Target in Refractory B Cell Malignancies
Lee J, Geng H, Chen Z, Klemm L, Cosgun K, Xiao G, Masouleh B, Hurtz C, Parekh S, Kornblau S, Melnick A, Abbas A, Paietta E, Müschen M. CD25 Enables Oncogenic BCR Signaling and Represents a Therapeutic Target in Refractory B Cell Malignancies. Blood 2016, 128: 4088. DOI: 10.1182/blood.v128.22.4088.4088.Peer-Reviewed Original ResearchB-cell malignanciesB-cell tumorsB cell receptorPoor clinical outcomeCell tumorsCell malignanciesClinical outcomesCD25 expressionB-cell leukemiaT cellsClinical cohortCell leukemiaTherapeutic targetB cellsRefractory B-cell malignanciesCell receptorExpression levelsMultiple B-cell malignanciesTumor clonesRegulatory T cellsHigh expression levelsDivergent clinical outcomesBCR signalingHuman B-cell malignanciesB-cell lymphoma cellsPre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition
Köhrer S, Havranek O, Seyfried F, Hurtz C, Coffey G, Kim E, ten Hacken E, Jäger U, Vanura K, O'Brien S, Thomas D, Kantarjian H, Ghosh D, Wang Z, Zhang M, Ma W, Jumaa H, Debatin K, Müschen M, Meyer L, Davis R, Burger J. Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition. Leukemia 2016, 30: 1246-1254. PMID: 26847027, PMCID: PMC5459356, DOI: 10.1038/leu.2016.9.Peer-Reviewed Original ResearchConceptsB-cell acute lymphoblastic leukemiaSpleen tyrosine kinaseAcute lymphoblastic leukemiaPI3K/AktLymphoblastic leukemiaTherapeutic targetPrecursor B-cell acute lymphoblastic leukemiaPromising new therapeutic targetNew therapeutic targetsGene expression signaturesImmune phenotypeImportant downstream mediatorSYK inhibitionMouse modelPre-BCR signalingReceptor signalingDownstream mediatorExpression signaturesGenetic disruptionLeukemiaExquisite dependencyTyrosine kinaseAktFOXO1Signaling
2015
Identification of BCL6 As a Therapeutic Target in RAS-Driven Acute Lymphoblastic Leukemia
Li Q, Hurtz C, Shojaee S, Chen Z, Geng H, Xiao G, Loh M, Ye B, Melnick A, Muschen M. Identification of BCL6 As a Therapeutic Target in RAS-Driven Acute Lymphoblastic Leukemia. Blood 2015, 126: 556. DOI: 10.1182/blood.v126.23.556.556.Peer-Reviewed Original ResearchTime of relapseAcute lymphoblastic leukemiaLymphoblastic leukemiaTherapeutic targetNOD/SCID miceInhibition of BCL6Conventional cytotoxic therapyBCL6 functionComplementary mouse modelsTransplant recipient miceTranscriptional repressor BCL6P53-dependent senescenceMEK inhibitor PD325901Patient-derived cellsInitial remissionTransplant recipientsLeukemia relapseInitial diagnosisPathway lesionsCytotoxic therapyRecipient miceSCID miceSame patientFatal leukemiaMouse modelErk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia
Shojaee S, Caeser R, Buchner M, Park E, Swaminathan S, Hurtz C, Geng H, Chan LN, Klemm L, Hofmann WK, Qiu YH, Zhang N, Coombes KR, Paietta E, Molkentin J, Koeffler HP, Willman CL, Hunger SP, Melnick A, Kornblau SM, Müschen M. Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia. Cancer Cell 2015, 28: 114-128. PMID: 26073130, PMCID: PMC4565502, DOI: 10.1016/j.ccell.2015.05.008.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Transformation, NeoplasticDNA-Binding ProteinsDual Specificity Phosphatase 6Host Cell Factor C1HumansIntracellular Signaling Peptides and ProteinsMAP Kinase Signaling SystemMembrane ProteinsMiceMice, TransgenicMolecular Sequence DataPrecursor Cell Lymphoblastic Leukemia-LymphomaPrognosisProtein Serine-Threonine KinasesSmall Molecule LibrariesTranscription FactorsConceptsAcute lymphoblastic leukemiaLymphoblastic leukemiaPatient-derived preNegative feedback regulationPre-B cell cloneCell deathImmediate cell deathMouse modelSmall molecule inhibitorsTherapeutic targetAcute activationMalignant transformationCell clonesFeedback regulationOncogenic signalingMolecule inhibitorsStrong activationLeukemiaDeathERKPre-B-cell transformationCell transformationActivationOncogenic transformationVast majorityIdentification 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
2014
FOXM1 Mediates Drug-Resistance and Represents a Therapeutic Target in Pre-B Acute Lymphoblastic Leukemia
Buchner M, Park E, Klemm L, Geng H, Kopanja D, Raychaudhuri P, Muschen M. FOXM1 Mediates Drug-Resistance and Represents a Therapeutic Target in Pre-B Acute Lymphoblastic Leukemia. Blood 2014, 124: 790. DOI: 10.1182/blood.v124.21.790.790.Peer-Reviewed Original ResearchB cell developmentFOXM1 protein levelsAcute lymphoblastic leukemiaB cell progenitorsB cell precursorsCell developmentFOXO factorsRegulation of FoxM1BCR-ABL1Cell lineagesB-cell lineageBox transcription factor familyCell progenitorsProtein levelsEarly B cell developmentLymphoblastic leukemiaTranscription factor familyCell precursorsGene expression surveyFoxM1 downregulationNormal B cell developmentPre-B cell receptor checkpointFOXM1 expressionTherapeutic targetB cellsHarnessing 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 capacity
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) formationInhibitory 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
Identification of FoxM1 As Therapeutic Target in TKI-Resistant Ph+ ALL
Buchner M, Klemm L, Zhengshan C, Geng H, Muschen M. Identification of FoxM1 As Therapeutic Target in TKI-Resistant Ph+ ALL. Blood 2012, 120: 874. DOI: 10.1182/blood.v120.21.874.874.Peer-Reviewed Original ResearchB cell precursorsLymphoblastic leukemiaTherapeutic targetPhiladelphia chromosome-positive acute lymphoblastic leukemiaPositive acute lymphoblastic leukemiaARF peptidesCell precursorsTreatment of TKIMajority of patientsTime of diagnosisAcute lymphoblastic leukemiaPatient-derived xenograftsValid therapeutic targetEffects of TKIsPotential therapeutic agentForkhead box transcription factor familyCell cycleSuperoxide dismutase expressionG0/G1Thiostrepton treatmentTKI treatmentPoor outcomeCombination therapyFl miceClinical trialsITIM-Containing Inhibitory Receptors Are Required to Balance Oncogenic Signaling Strength in Ph+ ALL
Chen Z, Geng H, Buchner M, Klemm L, Hemati K, Shojaee S, Tak M, Coligan J, Carroll W, Willman C, Muschen M. ITIM-Containing Inhibitory Receptors Are Required to Balance Oncogenic Signaling Strength in Ph+ ALL. Blood 2012, 120: 291. DOI: 10.1182/blood.v120.21.291.291.Peer-Reviewed Original ResearchBCR-ABL1Leukemia cellsInhibitory receptorsLeukemia cell deathTherapeutic targetSurvival rateCellular senescenceAcute lymphoblastic leukemia cellsFree survival rateOverall survival rateG0/G1 cell cycle arrestMRNA levelsAdditional therapeutic targetsNOD-SCID miceNormal bone marrow samplesBone marrow samplesCycle arrestHalf of casesG1cell cycle arrestLymphoblastic leukemia cellsG1 cell cycle arrestCell deathColony forming assaysCOG trialsLeukemia regressionSuppressor of Cytokine Signaling (SOCS) Molecules Are Critical to Balance Oncogenic Signaling Strength in Ph+ ALL.
Chen Z, Geng H, Klemm L, Buchner M, Hemati K, Shojaee S, Alexander W, Carroll W, Willman C, Muschen M. Suppressor of Cytokine Signaling (SOCS) Molecules Are Critical to Balance Oncogenic Signaling Strength in Ph+ ALL. Blood 2012, 120: 2563. DOI: 10.1182/blood.v120.21.2563.2563.Peer-Reviewed Original ResearchBCR-ABL1Leukemia cellsTherapeutic targetSurvival rateP-STAT5Acute lymphoblastic leukemia cellsFree survival rateOverall survival rateHigh expression levelsG0/G1 cell cycle arrestRole of SOCS2Course of diseaseMRNA levelsAdditional therapeutic targetsNOD-SCID miceInducible deletionG1 cell cycle arrestLymphoblastic leukemia cellsExpression levelsCellular senescenceCOG trialsLeukemia regressionExpression of SOCS2Poor outcomeJAK/STAT pathway
2011
DUSP6-Mediated Negative Feedback to Oncogenic Tyrosine Kinase Signaling Prevents Excessive Accumulation of ROS and Enables Leukemia Cell Survival
Shojaee S, Buchner M, Geng H, Melnick A, Gery S, Molkentin J, Koeffler P, Muschen M. DUSP6-Mediated Negative Feedback to Oncogenic Tyrosine Kinase Signaling Prevents Excessive Accumulation of ROS and Enables Leukemia Cell Survival. Blood 2011, 118: 1479. DOI: 10.1182/blood.v118.21.1479.1479.Peer-Reviewed Original ResearchCellular senescenceEffects of BCIProtein levelsCpG methylation analysisLeukemia cellsOncogene-induced senescenceGene expression changesLineage leukemiaCpG methylation levelsOncogenic tyrosine kinasesPharmacological inhibitionTyrosine kinase activityActivation of p53Small molecule inhibitorsBone marrow progenitor cellsGenetic experimentsDUSP6 functionLeukemia cell survivalTherapeutic targetB-cell lymphoma cell linesMarrow progenitor cellsNormal growth kineticsHigh ROS levelsKinase activityPromoter region