2024
Therapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery
Chan A, Han L, Delaney C, Wang X, Mukhaleva E, Li M, Yang L, Pokharel S, Mattson N, Garcia M, Wang B, Xu X, Zhang L, Singh P, Elsayed Z, Chen R, Kuang B, Wang J, Yuan Y, Chen B, Chan L, Rosen S, Horne D, Müschen M, Chen J, Vaidehi N, Armstrong S, Su R, Chen C. Therapeutic targeting Tudor domains in leukemia via CRISPR-Scan Assisted Drug Discovery. Science Advances 2024, 10: eadk3127. PMID: 38394203, PMCID: PMC10889360, DOI: 10.1126/sciadv.adk3127.Peer-Reviewed Original ResearchConceptsTudor domainDrug discoveryRibosomal gene expressionMolecular dynamics simulationsDomain-focused CRISPR screeningDe novo drug discoveryCompound dockingAcetyltransferase complexCRISPR screensGenetic approachesLead inhibitorDynamics simulationsStructural genetics approachGene expressionH3K9 acetylationEpigenetic dysregulationSgf29Tile scansLeukemia progressionMultiple cancersDrug developmentDiscoveryH3K9DockingLeukemia
2023
Optogenetic Control of Oncogenic Signaling in B-Cell Malignancies
Kume K, Lee J, Cheng Z, Robinson M, Leveille E, Cosgun K, Chan L, Feng Y, Arce D, Khanduja D, Toomre D, Müschen M. Optogenetic Control of Oncogenic Signaling in B-Cell Malignancies. Blood 2023, 142: 4138. DOI: 10.1182/blood-2023-190926.Peer-Reviewed Original ResearchB-cell malignanciesB-cell lymphomaMature B-cell lymphomasB cell deathB cellsB cell developmentGenetic deletionMantle cell lymphomaNF-kB signalingBCR signal inhibitorsB cell precursorsCell of originCell viabilityChronic active BCRB cell survivalB cell receptor signalsHodgkin's diseaseMultiple myelomaNormal B cell developmentPlasma cellsBtk tyrosine kinaseCell lymphomaBurkitt's lymphomaNF-kBSmall molecule inhibitorsSTAT5-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-LCRepurposing 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 pathwayDynamic Recruitment of Inhibitory Complexes Controls Oncogenic Signaling in B-Cell Malignancies
Sun R, Lee J, Robinson M, Kume K, Ma N, Cosgun K, Chan L, Antoshkina I, Khanduja D, Leveille E, Katz S, Chen J, Paietta E, Vaidehi N, Müschen M. Dynamic Recruitment of Inhibitory Complexes Controls Oncogenic Signaling in B-Cell Malignancies. Blood 2023, 142: 719. DOI: 10.1182/blood-2023-189742.Peer-Reviewed Original ResearchB-cell malignanciesB-cell lymphomaHigher serum levelsMature B-cell lymphomasSoluble CD25Serum levelsOncogenic signalingMouse modelB cellsAggressive B-cell lymphomasAcceleration of diseaseActivation of inhibitoryPoor clinical outcomeCD25 surface expressionB cell subsetsRole of CD25Patient-derived xenograftsB cell populationsB-cell receptor signalingB-cell leukemiaGenetic mouse modelsKnockin mouse modelCell deathMature B cell populationClinical outcomesComputational 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 stressMYC to BCL6 State-Transitions Determine Cell Size and Metabolic Fluctuations and Define a Novel Biorhythm in B-Cell Malignancies
Cheng Z, Kume K, Müschen M. MYC to BCL6 State-Transitions Determine Cell Size and Metabolic Fluctuations and Define a Novel Biorhythm in B-Cell Malignancies. Blood 2023, 142: 2769. DOI: 10.1182/blood-2023-190972.Peer-Reviewed Original ResearchGerminal center-derived B-cell lymphomaB cell developmentCell size fluctuationsCell cycleImmunoglobulin light chain gene recombinationDNA damage-induced apoptosisDistinct cellular statesNormal B cell developmentDamage-induced apoptosisExit cell cycleCell sizeB cell transitionGene expression profilesQuiescent phenotypeOncogenic tyrosine kinasesCell cycle arrestActivation of autophagySingle-cell sortingCellular statesCell divisionHigher glycolysis activityMYC transcriptionB cell cycleSuppression of glycolysisExpression profilesGenetic Knockin Approaches to Reconstructing DLBCL-Subtypes from Human Germinal Center B-Cells
Khanduja D, Robinson M, Arce D, Klemm L, Leveille E, Kothari S, Caeser R, Hodson D, Müschen M. Genetic Knockin Approaches to Reconstructing DLBCL-Subtypes from Human Germinal Center B-Cells. Blood 2023, 142: 1627. DOI: 10.1182/blood-2023-190634.Peer-Reviewed Original ResearchSecondary lymphoid organsGerminal center B cellsMYD88 L265P mutationLymphoid organsLymph nodesB cellsL265P mutationHuman germinal center B cellsDLBCL subtypesNSG miceTonsillar germinal center B cellsLymphoma developmentPreclinical testingLymphoid tissue inducer cellsTransgenic expressionPoor clinical outcomeWild-type mutationsGenetic mouse modelsExon 5GC B cellsNBSGW miceClinical outcomesLTi cellsLymphoid folliclesInducer cellsSeparation 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 mechanismDevelopment of Chimeric Antigen Receptor (CAR) T Cells Targeting MET in Lymphomas and Solid Tumors
Chen P, Raghunandan R, Müschen M, Katz S. Development of Chimeric Antigen Receptor (CAR) T Cells Targeting MET in Lymphomas and Solid Tumors. Blood 2023, 142: 6805. DOI: 10.1182/blood-2023-186161.Peer-Reviewed Original ResearchDiffuse large B-cell lymphomaB-cell lymphomaChimeric antigen receptor T cellsAntigen receptor T cellsLarge B-cell lymphomaReceptor T cellsT cellsLymphoma cell linesHGF/METMET expressionOCI-Ly3CD69 expressionDLBCL cell linesCD19-CARSolid tumorsCell linesAnti-Met monoclonal antibodiesCD19 CAR T cellsNegative diffuse large B-cell lymphomaRefractory B-cell malignanciesLoss of CD19B-cell depletionActivation marker CD69Classic Hodgkin lymphomaJurkat T cellsPTEN Counter Balances mTORC1 and PI3K Activities to Maintain Metabolic Homeostasis of B-ALL
Liu H, Song J, Robinson M, Xiao G, Müschen M. PTEN Counter Balances mTORC1 and PI3K Activities to Maintain Metabolic Homeostasis of B-ALL. Blood 2023, 142: 2780. DOI: 10.1182/blood-2023-184800.Peer-Reviewed Original ResearchThe Transcriptional Landscape of Ph+B-ALL Is Orchestrated By Long-Range Enhancer-Promoter Interactions and the Coordinated Action of Phosphorylation-Dependent and Phosphorylation-Independent Transcription Factors
Ng H, Robinson M, Malysheva V, Deniz O, Crump N, Cosgun K, Helian K, Spivakov M, Müschen M, Feldhahn N. The Transcriptional Landscape of Ph+B-ALL Is Orchestrated By Long-Range Enhancer-Promoter Interactions and the Coordinated Action of Phosphorylation-Dependent and Phosphorylation-Independent Transcription Factors. Blood 2023, 142: 2779. DOI: 10.1182/blood-2023-173435.Peer-Reviewed Original ResearchTranscription factorsTranscriptional programsEnhancer signatureGene expressionChromatin interactionsTranscriptional changesTyrosine kinaseAdditional transcription factorsMotif enrichment analysisPromoter-enhancer interactionsCis-regulatory elementsEnhancer-promoter interactionsPromoter capture HiNon-promoter regionsUnique transcriptional programGene expression changesCoordinated actionMurine B cell precursorsOncogenic tyrosine kinasesEnhancer usageActive chromatinActive genesEnhancer landscapeTranscriptional landscapeActive enhancersMechanistic Elucidation of the Tumor-Promoting Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 in B-Cell Receptor Signaling in Mantle Cell Lymphoma
Xavier S, Nguyen V, Khairnar V, Phan A, Yang L, Nelson M, Tseng E, Li A, Song J, Weisenburger D, Chan W, Müschen M, Ngo V. Mechanistic Elucidation of the Tumor-Promoting Role of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 in B-Cell Receptor Signaling in Mantle Cell Lymphoma. Blood 2023, 142: 720. DOI: 10.1182/blood-2023-175064.Peer-Reviewed Original ResearchMantle cell lymphomaCell adhesion molecule-1Adhesion molecule-1Proximity ligation assayMCL linesN-terminal domainLipid raft formationSHP-1BCR activationCell lymphomaMolecule-1B cellsCell linesCarcinoembryonic antigen-related cell adhesion molecule 1F-actinRaft formationTerminal ligand-binding domainPhosphorylation levelsGenome-wide screenB-cell receptor signalingRecruitment of SykImmunoreceptor tyrosine-based inhibitory motifPathogenesis of MCLTyrosine-based inhibitory motifCell receptor signalingNegative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression
Ecker V, Brandmeier L, Stumpf M, Giansanti P, Moreira A, Pfeuffer L, Fens M, Lu J, Kuster B, Engleitner T, Heidegger S, Rad R, Ringshausen I, Zenz T, Wendtner C, Müschen M, Jellusova J, Ruland J, Buchner M. Negative feedback regulation of MAPK signaling is an important driver of chronic lymphocytic leukemia progression. Cell Reports 2023, 42: 113017. PMID: 37792532, DOI: 10.1016/j.celrep.2023.113017.Peer-Reviewed Original ResearchConceptsMitogen-activated protein kinaseChronic lymphocytic leukemiaCLL cellsMitochondrial reactive oxygen speciesChronic lymphocytic leukemia progressionApoptotic cell deathPoor clinical prognosisCLL cell survivalSmall molecule inhibitorsNegative feedback regulationProtein kinaseReactive oxygen speciesMAPK signalingMAPK activityPromising treatment conceptClinical prognosisClinical challengeLymphocytic leukemiaCell survivalAcute activationCell deathDNA damageDUSP6Treatment conceptFeedback regulationPD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma
Wartewig T, Daniels J, Schulz M, Hameister E, Joshi A, Park J, Morrish E, Venkatasubramani A, Cernilogar F, van Heijster F, Hundshammer C, Schneider H, Konstantinidis F, Gabler J, Klement C, Kurniawan H, Law C, Lee Y, Choi S, Guitart J, Forne I, Giustinani J, Müschen M, Jain S, Weinstock D, Rad R, Ortonne N, Schilling F, Schotta G, Imhof A, Brenner D, Choi J, Ruland J. PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma. Nature Cancer 2023, 4: 1508-1525. PMID: 37723306, PMCID: PMC10597841, DOI: 10.1038/s43018-023-00635-7.Peer-Reviewed Original ResearchConceptsPD-1T-NHLAP-1 activityT-cell non-Hodgkin lymphomaImmune checkpoint receptor PD-1Cell non-Hodgkin lymphomaCheckpoint receptor PD-1Receptor PD-1Non-Hodgkin lymphomaT-cell lymphomaT-cell malignanciesPrimary patient samplesTractable mouse modelAdvanced diseaseInferior prognosisProtein-1 transcription factorT cellsCell lymphomaMouse modelCell malignanciesATP citrate lyase activityACLY inhibitionPatient samplesTumor suppressive mechanismKey tumor suppressorCD25 recruits inhibitory phosphatases for feedback control of B-cell receptor signaling
Sun R, Lee J, Robinson M, Kume K, Cosgun K, Chan L, Leveille E, Geng H, Vykunta V, Shy B, Marson A, Meffre E, Müschen M. CD25 recruits inhibitory phosphatases for feedback control of B-cell receptor signaling. The Journal Of Immunology 2023, 210: 154.23-154.23. DOI: 10.4049/jimmunol.210.supp.154.23.Peer-Reviewed Original ResearchAntigen-experienced B cellsB cellsEarly B cell developmentGerminal centersB cell developmentSpontaneous germinal centersCD25 surface expressionAutoreactive B cellsRole of CD25B cell toleranceB-cell receptor signalingB-cell leukemiaB cell receptorAutoantibody productionCD25Cell toleranceGenetic ablationReceptor signalingBCR signalingOncogenic signalingInhibitorySuccessful initiationSignalingNegative selectionAutoimmunityβ-catenin engages IKZF factors to control lymphopoiesis
Cosgun K, Jumaa H, Robinson M, Xu L, Xiao G, Arce D, Khanduja D, Chan L, Lee J, Schjerven H, Jellusova J, Müschen M. β-catenin engages IKZF factors to control lymphopoiesis. The Journal Of Immunology 2023, 210: 65.09-65.09. DOI: 10.4049/jimmunol.210.supp.65.09.Peer-Reviewed Original ResearchΒ-cateninZinc finger transcription factorFinger transcription factorDramatic nuclear accumulationGSK3β-dependent phosphorylationT cell signalingT cell developmentTCF factorsRepressive complexesTranscriptional controlEnhancer clusterInteractome studiesTranscriptional activationΒ-catenin activationCommon oncogenic driversInhibition of GSK3βTranscription factorsNegative regulationMesenchymal lineagesNuclear accumulationCell deathMYCT-lymphoid malignancyΒ-catenin expressionPromotes ProliferationEpigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1‐EEF1A1 Axis
Li M, Yang L, Chan A, Pokharel S, Liu Q, Mattson N, Xu X, Chang W, Miyashita K, Singh P, Zhang L, Li M, Wu J, Wang J, Chen B, Chan L, Lee J, Zhang X, Rosen S, Müschen M, Qi J, Chen J, Hiom K, Bishop A, Chen C. Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1‐EEF1A1 Axis. Advanced Science 2023, 10: 2206584. PMID: 37075745, PMCID: PMC10265057, DOI: 10.1002/advs.202206584.Peer-Reviewed Original ResearchConceptsProtein translation machineryHistone H4 acetylationOncogenic transcription factorNuA4 histoneChromatin remodelersGene bodiesEpigenetic networksTranslation machineryATPase componentEpigenetic controlTumor progressionCRISPR screensTranscription factorsH4 acetylationEpigenetic dysregulationRUVBL1Oncogenic signalingProtein synthesisPatient-derived samplesMYCPharmacological inhibitionEEF1A1 expressionMultiple cancersNovel opportunitiesDynamic interplayArtemis 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 inhibitionProliferation