2024
Identification of Nuclear NAD+ Salvage As a Therapeutic Vulnerability in B-Lymphoid Malignancies
Robinson M, Li Q, Zhang C, Zhan C, Cheng Z, Kume K, Cosgun K, Kothari S, Agadzhanian N, Nakada D, Müschen M. Identification of Nuclear NAD+ Salvage As a Therapeutic Vulnerability in B-Lymphoid Malignancies. Blood 2024, 144: 4164-4164. DOI: 10.1182/blood-2024-205729.Peer-Reviewed Original ResearchB-ALL cell linesB-ALLB cellsCell linesTherapeutic vulnerabilitiesGene dependenciesNAD+ synthesisMature B-cell lymphomasElimination of B cellsTreatment of B-ALLNAD+ salvageChemotherapy-based regimensEffects of NAMPT inhibitionB-cell depletionB-cell lymphomaB-lymphoid malignanciesB-ALL cellsNAMPT inhibitorsInhibition of NAMPTATP-utilizing enzymesNAD+ salvage pathwayDrug repurposing platformNAD biosynthetic pathwayNear-complete ablationDe novo pathwayIdentification of High-Efficiency β-Catenin Protein Degradation As Critical Vulnerability in B-Cell Malignancies
Cosgun K, Robinson M, Agadzhanian N, Cheng Z, Oulghazi S, Berning P, Fonseca-Arce D, Kume K, Fontaine J, Chan L, Lee J, Yu F, Qian Z, Song J, Chan W, Chen J, Taketo M, Schjerven H, Müschen M. Identification of High-Efficiency β-Catenin Protein Degradation As Critical Vulnerability in B-Cell Malignancies. Blood 2024, 144: 4125-4125. DOI: 10.1182/blood-2024-208125.Peer-Reviewed Original ResearchProtein degradation pathwaysB-ALL cellsProtein degradationRepression of MYCTranscriptional activity of MYCCell deathAcute cell deathLoss of colony formationChIP-seq analysisActive enhancer marksB-cell malignanciesSuper-enhancer regionsActivation of MYCIkaros transcription factorB-lymphoid cellsCell linesB cell identityDefective protein degradationB-cateninNon-lymphoid cell linesDegradation pathwayMantle cell lymphomaProtein levelsB-ALLChIP-seqPKCδ-Mediated Phosphorylation of CD25 Initiates Feedback Control of Oncogenic Tyrosine Kinases in Acute Lymphoblastic Leukemia
Sun R, Lee J, Artadji D, Robinson M, Kume K, Cheng Z, Cosgun K, Chan L, Leveille E, Ma N, Geng H, Paietta E, Vaidehi N, Müschen M. PKCδ-Mediated Phosphorylation of CD25 Initiates Feedback Control of Oncogenic Tyrosine Kinases in Acute Lymphoblastic Leukemia. Blood 2024, 144: 632-632. DOI: 10.1182/blood-2024-211038.Peer-Reviewed Original ResearchB-ALL cellsPatient-derived xenograftsPh+ B-ALLPh-like B-ALLAntibody-drug conjugatesB-ALL casesB-ALLCre-mediated deletionOncogenic tyrosine kinasesBCR-ABL1Tyrosine kinase signalingSurface expressionColony formation capacityCD25 mRNACell surface expression of CD25Tyrosine kinaseGenetic deletionSurface expression of CD25Oncogenic tyrosine kinase signalingKinase signalingOncogene BCR-ABL1Transplant recipient miceControl ADCNegative feedback regulationExpression of CD25
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
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 leukemiaPharmacological Targeting of PI3K-Dependent Central Tolerance Mechanisms in Refractory Pre-Germinal Center B-Cell Malignancies
Kume K, Lee J, Chan L, Robinson M, Cosgun K, Meffre E, Müschen M. Pharmacological Targeting of PI3K-Dependent Central Tolerance Mechanisms in Refractory Pre-Germinal Center B-Cell Malignancies. Blood 2021, 138: 2267. DOI: 10.1182/blood-2021-149806.Peer-Reviewed Original ResearchCentral tolerance mechanismsMantle cell lymphomaB-cell malignanciesAutoreactive B cellsB cellsB cell developmentB cell receptorEarly B cell developmentB-ALLClinical cohortPharmacological targetingPathological signalingU-CLLNormal B-cell activationAutoreactive B cell receptorsRefractory B-ALLSequential treatment regimensPI3KNegative B cell selectionChronic lymphocytic leukemiaLarge clinical cohortB cell activationB-cell tumorsHuman B lymphopoiesisB cell selectionBeta-Catenin Forms Repressive Complexes with Ikzf1 and Ikzf3 to Orchestrate Tumor-Suppression in B-Cell Malignancies
Cosgun K, Robinson M, Chan L, Hur M, Leveille E, Song J, Chan W, Müschen M. Beta-Catenin Forms Repressive Complexes with Ikzf1 and Ikzf3 to Orchestrate Tumor-Suppression in B-Cell Malignancies. Blood 2021, 138: 29. DOI: 10.1182/blood-2021-148597.Peer-Reviewed Original ResearchB-cell malignanciesΒ-catenin activationΒ-cateninOncogenic Wnt/β-catenin signalingMalignant B-lymphoid cellsGenetic deletionRefractory B-ALLTranscriptional repressionB-cell lymphomaTumor suppressionWnt/β-catenin signalingΒ-catenin/TCF complexMature B-cell malignanciesB-lymphoid cellsCancer cell linesΒ-catenin signalingClonal fitnessOverall survivalLeukemia burdenNSG miceB-ALLCell cycle arrestNuclear β-cateninPan-cancer analysisFrequent lesions
2019
Autonomous Ca2+ Oscillations Reflect Oncogenic Signaling in B-ALL Cells
Kume K, Chen L, Lee J, Müschen M. Autonomous Ca2+ Oscillations Reflect Oncogenic Signaling in B-ALL Cells. Blood 2019, 134: 1253. DOI: 10.1182/blood-2019-130708.Peer-Reviewed Original ResearchBCR-ABL1Stromal interaction molecule 1Activation of NFATc1B cell receptorOncogenic kinase activityAutonomous Ca2Oncogenic signalingB cellsOscillatory Ca2Deletion of Stim1Poor clinical outcomeBCR-ABL1 kinase activityRole of SOCENormal B cellsCre-mediated deletionStrong cytotoxic responseStore-operated Ca2B cell survivalOncogenic kinasesClinical outcomesHodgkin's lymphomaB-ALLPump inhibitorsMouse modelKinase activity
2018
Autonomous Ca2+ Oscillations Reflect Oncogenic BCR-Signaling in Multiple B-Cell Malignancies and Are Essential for Survival and Proliferation
Kume K, Chen L, Lee J, Muschen M. Autonomous Ca2+ Oscillations Reflect Oncogenic BCR-Signaling in Multiple B-Cell Malignancies and Are Essential for Survival and Proliferation. Blood 2018, 132: 1373. DOI: 10.1182/blood-2018-99-117315.Peer-Reviewed Original ResearchAutonomous Ca2B-cell malignanciesBCR signalingProliferation signalsTime of diagnosisExpression levelsINCA-6B-ALLCell deathMantle cell lymphomaMedian expression levelBCR-ABL1Store-operated Ca2Cell lymphomaHigh expression levelsGenetic experimentsT-cell factorMyeloma cellsPatient-derived xenograft modelsMultiple B-cell malignanciesSurvival signalsFunctional BCRSTIM1/2Relapse-free survivalB-cell lymphoma cellsLgr5 Enables Positive B-Cell Selection and Tumor-Initiation in B-Cell Malignancies
Cosgun K, Deb G, Yang X, Xiao G, Sadras T, Auer F, Lee J, Abarientos A, Mangolini M, Aghajanirefah A, Geng H, Jumaa H, Polson A, Clevers H, Muschen M. Lgr5 Enables Positive B-Cell Selection and Tumor-Initiation in B-Cell Malignancies. Blood 2018, 132: 547. DOI: 10.1182/blood-2018-99-116956.Peer-Reviewed Original ResearchB-cell malignanciesB-cell lineageAntibody-drug conjugatesLeukemia-initiating cellsTransplant recipientsB-ALLSurface expressionCancer stem cell markersWorse overall survivalMature B cell poolPoor clinical outcomeSingle-agent treatmentΒ-cateninB cell poolB cell selectionStem cell markersΒ-catenin activationΒ-catenin target genesLGR5 overexpressionLIC frequencyOverall survivalLeukemia burdenClinical outcomesEnvironmental antigensRecipient mice
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