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 pathwayMechanism of Negative Feedback Regulation of Oncogenic BCR-Signaling in Mature B-Cell Lymphoma
Sun R, Lee J, Robinson M, Kume K, Zhan C, Cheng Z, Cosgun K, Chan L, Leveille E, Kothari S, Katz S, Ma N, Vykunta V, Shy B, Hodson D, Marson A, Vaidehi N, Müschen M. Mechanism of Negative Feedback Regulation of Oncogenic BCR-Signaling in Mature B-Cell Lymphoma. Blood 2024, 144: 3003-3003. DOI: 10.1182/blood-2024-211693.Peer-Reviewed Original ResearchB-cell lymphomaGC B cellsB-cell lymphoma cellsB cellsBCR signalingGerminal centersProteolytic cleavageNK cellsLymphoma cellsMantle cell lymphoma xenograftsAggressive B-cell lymphomasMature B-cell lymphomasB-cell lymphoma subtypesGerminal center B cellsSpontaneous germinal centersGlobal phosphoproteomic studiesActivation marker CD69Aggressiveness of diseaseCD25 surface expressionMechanism of negative feedback regulationB cell autoimmunityFollicular dendritic cellsHuman germinal centerCa2+ oscillationsExpressed increased levelsTargeting β-Catenin Protein Degradation in Refractory B-Cell Malignancies
Cosgun K, Robinson M, Agadzhanian N, Berning P, Fonseca-Arce D, Leveille E, Kothari S, Davids M, Jellusova J, Müschen M. Targeting β-Catenin Protein Degradation in Refractory B-Cell Malignancies. Blood 2024, 144: 1412. DOI: 10.1182/blood-2024-208598.Peer-Reviewed Original ResearchProtein degradationRepression of MYCTranscriptional repression of MYCTranscriptional repressionPromote survivalProteasome inhibitorsProtein degradation pathwaysCell typesN-terminal residuesInduce cell deathRefractory B-cell malignanciesB-cateninB-cell malignanciesRNAi screenInteractome studiesB cell selectionRepressive complexesGene dependenciesProteasomal degradationB cellsChemogenomic screensProteasome inhibitor bortezomibActivated mycDeletion of Ctnnb1Cell deathTuning Responses to Polatuzumab Vedotin in B-cell Lymphoma.
Leveille E, Kothari S, Cosgun K, Mlynarczyk C, Müschen M. Tuning Responses to Polatuzumab Vedotin in B-cell Lymphoma. Cancer Discovery 2024, 14: 1577-1580. PMID: 39228298, DOI: 10.1158/2159-8290.cd-24-0644.Peer-Reviewed Original ResearchDependence of lymphopoiesis on efficient β-catenin degradation
Cosgun K, Jumaa H, Robinson M, Klemm L, Oulghazi S, Fonseca-Arce D, Xu L, Xiao G, Khanduja D, Chan L, Lee J, Kume K, Song J, Chan W, Chen J, Taketo M, Kothari S. Dependence of lymphopoiesis on efficient β-catenin degradation. The Journal Of Immunology 2024, 212: 1195_4936-1195_4936. DOI: 10.4049/jimmunol.212.supp.1195.4936.Peer-Reviewed Original ResearchIkaros zinc fingersLymphoid cellsB-cateninChIP-seq analysisSuppression of MYC expressionRegulate lineage specificationInduce cell deathConstitutively low levelsDeletion of ApcChIP-seqTcf factorsZinc fingerProteasomal degradationBinding motifNucleosome remodelingDestruction complexSpecific genesWnt/b-catenin pathwayLineage specificationCell deathMYC expressionSuperenhancersLymphoid developmentEpithelial lineageEpithelial cells
2023
Separation of B- and T-Cell-Specific Signaling Molecules Prevents Oncogenic Transformation in Lymphoid Malignancies
Ketzer F, Klemm L, Robinson M, Loucks C, Arce D, Cosgun K, Kothari S, Müschen M. Separation of B- and T-Cell-Specific Signaling Molecules Prevents Oncogenic Transformation in Lymphoid Malignancies. Blood 2023, 142: 1396. DOI: 10.1182/blood-2023-189221.Peer-Reviewed Original ResearchKinase ZAP70Transcriptional regulationTranscription factorsKinase SykDownstream activationT-cell signaling proteinsCRISPR/Cas9-mediated knockoutComparative proteomic analysisNegative selectionFunction of proteinsWild-type cellsCas9-mediated knockoutCo-expressed proteinsPre-malignant cellsT cell linesCellular fitnessTranscription machinerySLP-76Signaling proteinsMalignant transformationSignal transductionAberrant transcriptionProteomic analysisChIP-qPCRNovel key mechanismRepurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies
Cosgun K, Robinson M, Oulghazi S, Xu L, Xiao G, Chan L, Lee J, Kume K, Leveille E, Arce D, Khanduja D, Feldhahn N, Song J, Chan W, Chen J, Taketo M, Schjerven H, Jellusova J, Kothari S, Davids M, Müschen M. Repurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies. Blood 2023, 142: 2818. DOI: 10.1182/blood-2023-190522.Peer-Reviewed Original ResearchFavorable safety profileSmall molecule inhibitorsT-lymphoid malignancyΒ-catenin degradationLymphoid malignanciesΒ-cateninInteractome studiesSafety profileClinical trialsMolecule inhibitorsLow nanomolar concentrationsΒ-catenin accumulationSolid tumorsRefractory B-cell malignanciesCell deathPK/PD profilesZinc finger proteinRefractory lymphoid malignanciesChIP-seq analysisPhase 2 trialMYC target genesT-cell lymphomaColony formationRapid nuclear accumulationWnt/β-catenin pathwayComputational Discovery and Validation of NAD+ Biosynthesis As Unique Vulnerability in B-Lymphoid Malignancies
Li Q, Robinson M, Leveille E, Zhang C, Sun R, Cheng Z, Kume K, Cosgun K, Kothari S, Khanduja D, Nakada D, Müschen M. Computational Discovery and Validation of NAD+ Biosynthesis As Unique Vulnerability in B-Lymphoid Malignancies. Blood 2023, 142: 418. DOI: 10.1182/blood-2023-190269.Peer-Reviewed Original ResearchSmall molecule inhibitorsDrug discovery toolNAMPT inhibitorsCompound screenCell type-specific targetsCell linesMolecule inhibitorsPurine/pyrimidine metabolismTumor cell linesEnergy metabolismSalvage biosynthesis pathwaySolid tumor cell linesB cell developmentCellular energy metabolismB cell signalingAmino acid metabolismCell cycle arrestDiscovery toolDepletion of metabolitesBiosynthesis pathwayCompetitive fitnessRate-limiting enzymeNAMPT deletionConditional mouse modelEnergy stress