2023
Computational 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 stressDevelopment 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 cellsMechanistic 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 signalingArtemis 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
2019
Effective Novel Fto Inhibitors Show Potent Anti-Cancer Efficacy and Suppress Drug Resistance
Su R, Dong L, Li Y, Han L, Gao M, Wunderlich M, Deng X, Li H, Gao L, Li C, Robison S, Tan B, Qing Y, Qin X, Prince E, Xie J, Qin H, Huang Y, Li W, Shen C, Sun J, Prakash K, Weng H, Huang H, Chen Z, Zhang B, Wu X, Olsen M, Müschen M, Marcucci G, Ravi S, Li L, Yang C, Li Z, Mulloy J, Wei M, Horne D, Chen J. Effective Novel Fto Inhibitors Show Potent Anti-Cancer Efficacy and Suppress Drug Resistance. Blood 2019, 134: 233. DOI: 10.1182/blood-2019-124535.Peer-Reviewed Original ResearchAML cell linesAnti-leukemic effectsAML cellsMouse modelDrug resistanceAcute myeloid leukemia patientsPotent anti-leukemic effectCell linesPotent anti-cancer efficacyAML cell viabilitySuppress drug resistanceAML mouse modelAnti-leukemia effectMyeloid leukemia patientsAnti-leukemic efficacyTransplantation mouse modelMurine AML cellsOnset of leukemiaFTO inhibitorsPotent therapeutic efficacyTyrosine kinase inhibitorsXenograft mouse modelAnti-leukemic activityFTO proteinAnti-AML efficacyLgr5 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 lineage
2015
Expression of B and T Lymphocyte Attenuator (BTLA) Correlates with CNS Metastasis and Adverse Prognosis in Activated B-Cell Lymphoma and Acute Lymphoblastic Leukemia
Geng H, Chen Z, Anderson S, Fraser E, Lu M, Lingjing C, Collins C, Markus M, Rubenstein J. Expression of B and T Lymphocyte Attenuator (BTLA) Correlates with CNS Metastasis and Adverse Prognosis in Activated B-Cell Lymphoma and Acute Lymphoblastic Leukemia. Blood 2015, 126: 3900. DOI: 10.1182/blood.v126.23.3900.3900.Peer-Reviewed Original ResearchPatient-derived cell linesLarge B-cell lymphomaB-cell lymphomaShorter overall survivalAcute lymphoblastic leukemiaHigh BTLA expressionBTLA expressionOverall survivalHigh-resolution array-based comparative genomic hybridizationMurine modelRecurrent copy number gainsDNA copy number aberrationsArray-based comparative genomic hybridizationCell linesCNS metastasisLymphoblastic leukemiaCopy number gainsB cell receptorComparative genomic hybridizationCopy number aberrationsPrimary central nervous system lymphomaGenomic changesCentral nervous system lymphomaTranscript levelsAggressive B-cell lymphomas
2013
Bruton′s Tyrosine Kinase Inhibitor Ibrutinib Interferes With Constitutive and Induced Pre-B Cell Receptor Signaling In B-Cell Acute Lymphoblastic Leukemia
Kim E, Koehrer S, Rosin N, Wang Z, Thomas D, Ravandi F, Kornblau S, Kantarjian H, O'Brien S, Estrov Z, Buggy J, Muschen M, Davis R, Burger J. Bruton′s Tyrosine Kinase Inhibitor Ibrutinib Interferes With Constitutive and Induced Pre-B Cell Receptor Signaling In B-Cell Acute Lymphoblastic Leukemia. Blood 2013, 122: 1399. DOI: 10.1182/blood.v122.21.1399.1399.Peer-Reviewed Original ResearchB cell receptorBruton's tyrosine kinasePre-BCR signalingInhibitor ibrutinibCalcium mobilizationCell linesBruton tyrosine kinase inhibitor ibrutinibB-cell acute lymphoblastic leukemiaGene expression profile analysisB-cell acute lymphoblastic leukemia cell linesEffects of ibrutinibAcute lymphoblastic leukemia cell lineAcute lymphoblastic leukemiaCell proliferationKinase inhibitor ibrutinibIntracellular calcium mobilizationLymphoblastic leukemia cell lineBTK inhibitor ibrutinibCalcium flux assaysB cell activationPre-B cell receptor signalingHalf maximal inhibitory concentrationV4 Expression BeadChipSensitive cell linesTyrosine kinase
2012
BCOR Is Involved in Myeloid Cell Growth Control by Regulating Hox Genes
Cao Q, Gery S, Shojaee S, Gearhart M, Bardwell V, Muschen M, Koeffler H. BCOR Is Involved in Myeloid Cell Growth Control by Regulating Hox Genes. Blood 2012, 120: 3445. DOI: 10.1182/blood.v120.21.3445.3445.Peer-Reviewed Original ResearchHox genesMyeloid cell differentiationCell differentiationCell linesIndividual Hox genesNormal hematopoiesisEssential developmental regulatorsStem cell stateOculofaciocardiodental syndromeEarly embryonic developmentCell growth controlStem cell functionTranscriptional repressive complexDownstream target genesTumor suppressor proteinGene expression profilesMesenchymal stem cell functionImmature hematopoietic cellsDevelopmental regulatorsPolycomb groupRepressive complexesHuman leukemic cell linesMost cell linesEmbryonic developmentSuppressor protein
2011
Compensatory Signaling From ROR1 and the Pre-B Cell Receptor Promote Survival of t(1;19) Acute Lymphoblastic Leukemia
Bicocca V, Chang B, Muschen M, Druker B, Tyner J. Compensatory Signaling From ROR1 and the Pre-B Cell Receptor Promote Survival of t(1;19) Acute Lymphoblastic Leukemia. Blood 2011, 118: 2466. DOI: 10.1182/blood.v118.21.2466.2466.Peer-Reviewed Original ResearchTyrosine kinaseAcute lymphoblastic leukemiaAkt activityPre-B cell receptor signalingCell linesLeukemogenic tyrosine kinasesProtein target identificationKinase inhibitor screenImmunoblot analysisCell receptor signalingCell viabilityKinase inhibitor screeningClinical trial contractsReceptor tyrosine kinasesTyrosine kinase activityPhospho-protein arraysSmall molecule inhibitorsROR1 knockdownSiRNA screeningAkt regulationLymphoblastic leukemiaDasatinib treatmentKinase domainPatient costsLeukemia patientsTargeting Survivin with YM155 As a Potential Therapy in Pediatric Acute Lymphoblastic Leukemia
Jemal A, Tyner J, Thayer M, Muschen M, Druker B, Chang B. Targeting Survivin with YM155 As a Potential Therapy in Pediatric Acute Lymphoblastic Leukemia. Blood 2011, 118: 2490. DOI: 10.1182/blood.v118.21.2490.2490.Peer-Reviewed Original ResearchPediatric acute lymphoblastic leukemiaAcute lymphoblastic leukemiaLymphoblastic leukemiaPatient samplesPrimary patientsCell linesActivation of apoptosisPediatric B-cell precursorHematopoietic stem cell transplantSelective survivin suppressantStandard intensive chemotherapyEarly phase I studiesSubset of patientsStem cell transplantPhase I studiesCommon pediatric malignancyB-cell malignanciesPrimary patient samplesB cell precursorsLymphoblastic cell linesAdditional therapyIntensive chemotherapyCell transplantCombination therapyPediatric malignancies
2010
ROR1 as a Therapeutic Target In E2A-PBX1-Positive Acute Lymphoblastic Leukemia
Bicocca V, Chang B, Muschen M, Druker B, Tyner J. ROR1 as a Therapeutic Target In E2A-PBX1-Positive Acute Lymphoblastic Leukemia. Blood 2010, 116: 539. DOI: 10.1182/blood.v116.21.539.539.Peer-Reviewed Original ResearchReceptor tyrosine kinase-like orphan receptor 1Acute lymphoblastic leukemiaPositive cell linesLymphoblastic leukemiaMononuclear cellsLeukemia patientsE2A-PBX1Cytogenetic subtypesCell linesPatient samplesPositive acute lymphoblastic leukemiaKinase inhibitorsB-cell precursor phenotypeTyrosine kinaseCommon pediatric cancerKinase-like orphan receptor 1Novel therapeutic toolTyrosine kinase expressionKinase inhibitor dasatinibOrphan receptor 1Aberrant tyrosine kinase activityCell viabilityMTS cell viability assaysPrimary cellsPathogenesis of leukemia
2009
The Pax5 Fusion Product Pax5-C20orf112 Causes Downregulation of Pre-B Cell Receptor Genes and Induces Differential Proliferation Patterns in B-Lymphoblastic Cell Lines.
Nowak D, Kawamata N, Niebuhr B, Nowak V, Mossner M, Nahar R, Thoennissen N, Iwanski G, Stocking C, Dugas M, Hofmann W, Müschen M, Koeffler P. The Pax5 Fusion Product Pax5-C20orf112 Causes Downregulation of Pre-B Cell Receptor Genes and Induces Differential Proliferation Patterns in B-Lymphoblastic Cell Lines. Blood 2009, 114: 1284. DOI: 10.1182/blood.v114.22.1284.1284.Peer-Reviewed Original ResearchPre-B cell receptor signalingPre-B cell receptorWild-type PAX5Cell receptor signalingImmunoglobulin heavy locusCandidate genesFusion productsCell linesFunctional pre-B cell receptorB-cell-specific transcription factor Pax5Spleen tyrosine kinaseGlobal gene expression analysisReceptor signalingPleckstrin homology domainRetroviral expression constructsB-cell linkerGroup of genesTranscription factor Pax5Promoter binding sitesAdaptor protein 1Receptor pathwayGene expression analysisEmpty vector controlGene expression microarraysCommon genomic lesionsInactivation of Pre-B Cell Receptor-Mediated Tumor Suppression by Aberrant Splicing in Ph+ Acute Lymphoblastic Leukemia.
Duy C, Sprangers M, Klemm L, Nahar R, Nowak D, Martinelli G, Hofmann W, Koeffler P, Jumaa H, Müschen M. Inactivation of Pre-B Cell Receptor-Mediated Tumor Suppression by Aberrant Splicing in Ph+ Acute Lymphoblastic Leukemia. Blood 2009, 114: 579. DOI: 10.1182/blood.v114.22.579.579.Peer-Reviewed Original ResearchPre-B cell receptorSH2 domainSplice factorsTumor suppressor functionAberrant splicingSplice variantsPre-B cell receptor signalingSequence analysisSplice siteSplice site mutationExon 16Suppressor functionCell receptorImportant protein domainsFunctional SH2 domainSite mutationSplice site selectionDetailed sequence analysisCell receptor signalingDominant negative effectDownstream effector moleculesCell linesMultiple splice variantsSplicing factorsProtein domains
2007
PAX5-Mediated Lineage Conversion and Expression of AID Accelerates Clonal Evolution and Initiates Darwinian Selection of BCR-ABL1-Mutants in Chronic Myeloid Leukemia.
Klemm L, Feldhahn N, Hoffmann T, Hofmann W, Jumaa H, Muschen M. PAX5-Mediated Lineage Conversion and Expression of AID Accelerates Clonal Evolution and Initiates Darwinian Selection of BCR-ABL1-Mutants in Chronic Myeloid Leukemia. Blood 2007, 110: 1005. DOI: 10.1182/blood.v110.11.1005.1005.Peer-Reviewed Original ResearchLineage conversionCell lineagesDarwinian selectionKinase domainB-cell lineageCell linesSequence analysisEnzyme AIDCML cell linesRetroviral expression constructsTranscription factor Pax5CML linesAID expressionDrug-resistant cellsCell lineage conversionTumor suppressor gene CDKN2ABlast crisis chronic myeloid leukemiaBCR-ABL1 kinase
2005
BCR–ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells
Klein F, Feldhahn N, Herzog S, Sprangers M, Mooster J, Jumaa H, Müschen M. BCR–ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells. Oncogene 2005, 25: 1118-1124. PMID: 16205638, DOI: 10.1038/sj.onc.1209133.Peer-Reviewed Original ResearchMeSH KeywordsAlternative SplicingAnimalsAntineoplastic AgentsBenzamidesCell Line, TumorCell LineageCell NucleusFusion Proteins, bcr-ablGene Expression ProfilingGene SilencingHumansIkaros Transcription FactorImatinib MesylateMicePiperazinesPrecursor B-Cell Lymphoblastic Leukemia-LymphomaProtein Kinase InhibitorsProtein-Tyrosine KinasesPyrimidinesConceptsLymphoid lineage commitmentLineage commitmentGenome-wide gene expression profilesAberrant splicingLymphoblastic leukemia cellsLeukemia cellsAberrant expressionGene expression profilesNormal B-cell subsetsCell linesPrecursor cell lineLineage identityLineage infidelityTranscription factorsRNA interferenceExpression profilesInducible expressionUndifferentiated phenotypeSplice variantsDefective expressionBCR-ABL1SplicingIk6ExpressionCells
2001
Oct-2 and Bob-1 deficiency in Hodgkin and Reed Sternberg cells.
Re D, Müschen M, Ahmadi T, Wickenhauser C, Staratschek-Jox A, Holtick U, Diehl V, Wolf J. Oct-2 and Bob-1 deficiency in Hodgkin and Reed Sternberg cells. Cancer Research 2001, 61: 2080-4. PMID: 11280769.Peer-Reviewed Original ResearchConceptsImmunoglobulin gene expressionH-RS cellsGene expressionOct-2 transcriptsOct-2 proteinTranscription factor Oct-2Primary H-RS cellsCell linesTranscription machineryBob-1Gene deregulationOctamer siteHodgkin's disease-derived cell linesImmunoglobulin genesNovel mechanismGerminal center B cellsCrippling mutationsClassical Hodgkin's diseaseProtein expressionB cellsTranscriptsExpressionProteinReed-Sternberg cellsCells
1999
Regulation of CD95 (APO‐1/ FAS) ligand and receptor expression in squamous‐cell carcinoma by interferon‐γ and cisplatin
Moers C, Warskulat U, Müschen M, Even J, Niederacher D, Josien R, Koldovsky U, Beckmann M, Häussinger D. Regulation of CD95 (APO‐1/ FAS) ligand and receptor expression in squamous‐cell carcinoma by interferon‐γ and cisplatin. International Journal Of Cancer 1999, 80: 564-572. PMID: 9935158, DOI: 10.1002/(sici)1097-0215(19990209)80:4<564::aid-ijc14>3.0.co;2-x.Peer-Reviewed Original ResearchConceptsSquamous cell carcinomaExpression of CD95LPrimary cell linesPrimary squamous cell carcinomaStroma cellsCD95L expressionAddition of CDDPCD95L mRNA levelsTumor-associated immunosuppressionHuman primary cell linesMRNA levelsEffect of cisplatinCell linesCD95 ligand expressionInvasive tumor tissuesAutologous lymphocytesCell carcinomaReceptor expressionSCC cellsSoluble receptorLigand expressionTumor tissueTumor samplesReceptor isoformsInvasion factors
1996
Induction of Mouse Embryonal Carcinoma Cell Differentiation and Activation of the Retinoic Acid Receptor β2 Promoter by 1,25-Dihydroxyvitamin D3
Müschen M, Sies H, Schulz W. Induction of Mouse Embryonal Carcinoma Cell Differentiation and Activation of the Retinoic Acid Receptor β2 Promoter by 1,25-Dihydroxyvitamin D3. Biological Chemistry 1996, 377: 703-710. PMID: 8960371, DOI: 10.1515/bchm3.1996.377.11.703.Peer-Reviewed Original ResearchConceptsRAR beta 2 promoterDihydroxyvitamin D3Carcinoma cellsRetinoic acidEffects of calcitriolDb-cAMPRetinoic Acid Receptor β2 PromoterEmbryonal carcinoma cellsCalcitriolRAR betaProtein kinase C. ThereforeInduces differentiationCalcitriol-induced differentiationReporter cell lineMouse embryonal carcinoma cellsDibutyryl cAMPCell linesProtein kinase CCollagen IVEmbryonal carcinoma cell differentiationCarcinoma cell differentiationFunctional TREsBeta-galactosidase activityActivationD3