2023
STAT5-Feedback Controls Distinct Metabolic States for Dynamic Transitions between Cellular Activation and Quiescence in Acute Lymphoblastic Leukemia
Kume K, Chen Z, Robinson M, Chan L, Leveille E, Cosgun K, Cheng Z, Arce D, Khanduja D, Graeber T, Müschen M. STAT5-Feedback Controls Distinct Metabolic States for Dynamic Transitions between Cellular Activation and Quiescence in Acute Lymphoblastic Leukemia. Blood 2023, 142: 2977. DOI: 10.1182/blood-2023-191006.Peer-Reviewed Original ResearchB-cell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaLymphoblastic leukemiaPharmacological inhibitionGenetic deletionCellular activationReceptor signalingCell deathBone marrow relapsePoor overall outcomePoor clinical outcomeLeukemia-initiating capacityOncogenic STAT5Mass spectrometry-based metabolomics analysisExpression levelsPhosphorylation of STAT5Flow cytometry analysisMetabolic statePositive MRDRole of mTORMarrow relapseAggressive courseClinical outcomesExcessive protein synthesisMetabolic outcomesImmunoglobulin Light Chains Control Permissiveness to Malignant B-Cell Transformation By RAS-Pathway Lesions
Chan L, Kume K, Hurtz C, Robinson M, Cosgun K, Müschen M. Immunoglobulin Light Chains Control Permissiveness to Malignant B-Cell Transformation By RAS-Pathway Lesions. Blood 2023, 142: 2974. DOI: 10.1182/blood-2023-190163.Peer-Reviewed Original ResearchJeKo-1 cellsB cell precursorsMature B cellsB cellsMantle cell lymphoma cellsCell lymphoma cellsGenetic ablationImmunoglobulin light chainsRAS activationOncogenic RASMalignant transformationB-cell acute lymphoblastic leukemiaConventional light chainsRAS pathwayLymphoma cellsCell deathOncogenic RAS activationLight chainAcute lymphoblastic leukemiaMature B-cell lymphomasTransgenic mouse modelB-cell lymphomaB-cell malignanciesMalignant B-cell transformationKappa-LCArtemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia
Ogana H, Hurwitz S, Hsieh C, Geng H, Müschen M, Bhojwani D, Wolf M, Larocque J, Lieber M, Kim Y. Artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia. Frontiers In Cell And Developmental Biology 2023, 11: 1134121. PMID: 37082620, PMCID: PMC10111164, DOI: 10.3389/fcell.2023.1134121.Peer-Reviewed Original ResearchMature B cell lineB-cell acute lymphoblastic leukemiaB cell linesDNA double-strand break repairChromosome breaksDouble-strand break repairDNA-PKcs complexDNA-PK inhibitorGene expression analysisCell linesAcute lymphoblastic leukemiaKey endonucleaseDNA-PKcsBreak repairNonhomologous endExpression analysisLymphoblastic leukemiaTherapeutic strategiesRefractory B-cell acute lymphoblastic leukemiaHigh-risk prePharmacological inhibitionNovel therapeutic strategiesIndirect suppressionDirect inhibitionProliferationPhosphorylation 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 ResearchB-cell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaLymphoblastic leukemiaTherapeutic targetLeukemiaSYK and ZAP70 kinases in autoimmunity and lymphoid malignancies
Leveille E, Chan LN, Mirza AS, Kume K, Müschen M. SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies. Cellular Signalling 2022, 94: 110331. PMID: 35398488, DOI: 10.1016/j.cellsig.2022.110331.Peer-Reviewed Original ResearchConceptsChronic lymphocytic leukemiaB-cell malignanciesT cell receptorB cell receptorB-cell chronic lymphocytic leukemiaPathological B-cellsPoor clinical outcomeAcute lymphoblastic leukemiaExpression of SykT lymphocyte developmentClinical outcomesAggressive diseaseActivation of NFATAutoimmune diseasesLymphoblastic leukemiaT lymphocytesLymphocytic leukemiaCell lymphomaLymphoid malignanciesB cellsPI3K-pathwayOncogenic driversMalignancyNegative selectionPremalignant cells
2021
Leveraging Pathway-Interference to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia
Chan L, Murakami M, Hurtz C, Kume K, Lee J, Cosgun K, Geng H, Izraeli S, Weinstock D, Müschen M. Leveraging Pathway-Interference to Overcome Drug-Resistance in Acute Lymphoblastic Leukemia. Blood 2021, 138: 616. DOI: 10.1182/blood-2021-149773.Peer-Reviewed Original ResearchB-ALLFl/flCancer typesOncogenic driversOncogenic pathwaysPharmacological reactivationPrincipal oncogenic driverMalignant transformationSpeakers bureauAcute lymphoblastic leukemiaGenetic lesionsERK pathwayTGFβ-Smad pathwaySignaling pathwaysMulti-step carcinogenesisERK agonistERK pathway activationOverall survivalNSG miceColorectal cancerInvasive cancerLymphoblastic leukemiaPreclinical studiesPathway interactionsFatal leukemiaPON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis
Pan L, Hong C, Chan LN, Xiao G, Malvi P, Robinson ME, Geng H, Reddy ST, Lee J, Khairnar V, Cosgun KN, Xu L, Kume K, Sadras T, Wang S, Wajapeyee N, Müschen M. PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2016553118. PMID: 33531346, PMCID: PMC7896313, DOI: 10.1073/pnas.2016553118.Peer-Reviewed Original ResearchConceptsTransplant recipient miceDNA double-strand breaksNormal B cell developmentDouble-strand breaksB cell developmentGenetic deletionB cellsLymphoid transcription factorsGlucose transporter GLUT1Gatekeeper functionGlucose uptakeRecipient miceTranscription factorsSomatic recombinationSynthetic lethalityB-cell acute lymphoblastic leukemiaCell developmentMetabolic gatekeeperRefractory B-ALLDeficient murineCell acute lymphoblastic leukemiaPoor clinical outcomeCell typesAcute lymphoblastic leukemiaGlucose transport
2019
Rationale for Targeting BCL6 in MLL-Rearranged B-ALL
Chan L, Hurtz C, Geng H, Ballabio E, Xiao G, Deb G, Khoury H, Armstrong S, Ernst P, Melnick A, Milne T, Müschen M. Rationale for Targeting BCL6 in MLL-Rearranged B-ALL. Blood 2019, 134: 1239. DOI: 10.1182/blood-2019-131565.Peer-Reviewed Original ResearchB-cell acute lymphoblastic leukemiaPharmacological inhibitionABT-199Group of patientsBCL6 expressionBone marrow biopsyPoor clinical outcomeAcute lymphoblastic leukemiaBCL2 inhibitor ABT-199BH3 mimetic ABT-199MLL gene rearrangementTransplant recipient miceMLL fusionsB-cell transformationClinical outcomesMarrow biopsyTreatment of MLLDismal outcomeLymphoblastic leukemiaRecipient miceNormal B cell developmentSelective vulnerabilityImmunohistochemical stainingInfant BSmall molecule inhibitorsLgr5 Functions As a Critical Negative Regulator of Wnt/β-Catenin Signaling and Is Essential for B-Lymphopoiesis and Malignant B-Cell Transformation
Cosgun K, Deb G, Yang X, Xiao G, Sadras T, Lee J, Chan L, Kume K, Yang L, Geng H, Chan J, Song J, Jumaa H, Polson A, Clevers H, Müschen M. Lgr5 Functions As a Critical Negative Regulator of Wnt/β-Catenin Signaling and Is Essential for B-Lymphopoiesis and Malignant B-Cell Transformation. Blood 2019, 134: 748. DOI: 10.1182/blood-2019-127263.Peer-Reviewed Original ResearchB-cell lineage acute lymphoblastic leukemiaWnt/β-catenin signalingΒ-catenin signalingNuclear β-cateninAntibody-drug conjugatesB cell developmentB cell survivalΒ-cateninB lymphopoiesisFunction of LGR5Median mRNA levelsTime of diagnosisPoor clinical outcomeRole of LGR5Acute lymphoblastic leukemiaB-cell lymphomaLeukemia initiating cellsWnt/β-cateninHigh surface expressionMalignant B-cell transformationCell linesB cell precursorsTypes of cancerHuman colon cancer cell linesB-cell lineageIdentification 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 changesRationale 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
Chen Z, Muschen M. Autoimmunity Checkpoints As Therapeutic Targets in B-Cell Malignancies. Blood 2018, 132: 1587. DOI: 10.1182/blood-2018-99-113674.Peer-Reviewed Original ResearchAutoreactive B-cell antigen receptorsB-cell malignanciesAcute lymphoblastic leukemiaAutoreactive B cellsB cellsCell malignanciesB cell antigen receptorNormal B cellsTypes of cancerAIC activationTargeted therapyAutoreactive clonesMalignant transformationTargeted activationAutoreactive B lymphocytesLymphocyte developmentPI3KB-cell lymphomaB-lymphoid malignanciesB-cell receptor signalingDrug-resistant leukemiaB-cell leukemiaB-cell tumorsCell deathNegative selectionPre-BCR Surrogate Light Chain Components VPREB1 and IGLL1 Function As Pre-BCR-Independent Tumor Suppressors in Acute Lymphoblastic Leukemia
Cosgun K, Hendriks R, Dickins R, Heisterkamp N, Muschen M. Pre-BCR Surrogate Light Chain Components VPREB1 and IGLL1 Function As Pre-BCR-Independent Tumor Suppressors in Acute Lymphoblastic Leukemia. Blood 2018, 132: 570. DOI: 10.1182/blood-2018-99-115522.Peer-Reviewed Original ResearchBCR-ABL1Transgenic miceSurrogate light chainTime of diagnosisTime of relapseDouble transgenic miceExerts tumor-suppressive effectsAcute lymphoblastic leukemiaB cell defectsDay of birthBCR-ABL1 tyrosine kinaseHigh surface levelsTumor-suppressive effectsPre-BCR expressionColony formation abilityPhosphorylation of BtkTumor suppressorBCR-ABL1 oncogeneEarly B cell developmentTumor suppressive functionLymphoblastic leukemiaCell cycle arrestFrequent lesionsSecondary lesionsSuppressive function
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
2016
BCL6 Is Critical to Overcome Oncogene-Induced Senescence in RAS-Mediated B Cell Transformation
Chan L, Hurtz C, Xiao G, Shojaee S, Caeser R, Geng H, Melnick A, Müschen M. BCL6 Is Critical to Overcome Oncogene-Induced Senescence in RAS-Mediated B Cell Transformation. Blood 2016, 128: 438. DOI: 10.1182/blood.v128.22.438.438.Peer-Reviewed Original ResearchDiffuse large B-cell lymphomaRAS-ERK signalingBCL6 expressionRole of BCL6Recipient micePhiladelphia chromosome-positive acute lymphoblastic leukemiaSTAT5 activityRAS-ERKLarge B-cell lymphomaAbsence of Bcl6Acute lymphoblastic leukemiaNovel mouse modelProto-oncogene Bcl6B-cell lymphomaNovel therapeutic avenuesTransplant recipient miceNovel mechanismMouse embryonic fibroblastsOncogene-Induced SenescenceP53-dependent senescenceB-cell transformationInitial remissionLeukemia relapseOverall survivalImatinib treatmentOncogenic Feedback Activation Between BCL6 and MLL Promotes Malignant Transformation in MLL-RearrangedAcute Lymphoblastic Leukemia
Hurtz C, Chan L, Ballabio E, Willman C, Carroll W, Armstrong S, Ernst P, Melnick A, Milne T, Müschen M. Oncogenic Feedback Activation Between BCL6 and MLL Promotes Malignant Transformation in MLL-RearrangedAcute Lymphoblastic Leukemia. Blood 2016, 128: 907. DOI: 10.1182/blood.v128.22.907.907.Peer-Reviewed Original ResearchFunction of Bcl6Lymphoblastic leukemiaMLL-AF4Expression levelsPhiladelphia chromosome-positive acute lymphoblastic leukemiaBCL6 levelsPharmacological inhibitionDiffuse large B-cell lymphomaLarge B-cell lymphomaChemotherapy drugs vincristineTime of diagnosisWorse clinical outcomesBCL6 expressionHigh expression levelsRelapse-free survivalAcute lymphoblastic leukemiaChronic myeloid leukemiaB-cell lymphomaHigh-risk regimenMLL-ENLTransplant recipient miceB cell precursorsReporter mouse modelWestern blot analysisClinical outcomesIdentification 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 characteristicsCorrection: Corrigendum: Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia
Chen Z, Shojaee S, Buchner M, Geng H, Lee J, Klemm L, Titz B, Graeber T, Park E, Tan Y, Satterthwaite A, Paietta E, Hunger S, Willman C, Melnick A, Loh M, Jung J, Coligan J, Bolland S, Mak T, Limnander A, Jumaa H, Reth M, Weiss A, Lowell C, Müschen M. Correction: Corrigendum: Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia. Nature 2016, 534: 138-138. PMID: 26958840, DOI: 10.1038/nature16997.Peer-Reviewed Original ResearchPre-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