2023
Dynamic 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 outcomesPD-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 suppressorIsoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms
Taghi Khani A, Kumar A, Sanchez Ortiz A, Radecki K, Aramburo S, Lee S, Hu Z, Damirchi B, Lorenson M, Wu X, Gu Z, Stohl W, Sanz I, Meffre E, Müschen M, Forman S, Koff J, Walker A, Swaminathan S. Isoform-specific knockdown of long and intermediate prolactin receptors interferes with evolution of B-cell neoplasms. Communications Biology 2023, 6: 295. PMID: 36941341, PMCID: PMC10027679, DOI: 10.1038/s42003-023-04667-8.Peer-Reviewed Original ResearchConceptsHuman B-cell malignanciesB-cell malignanciesB-cell neoplasmsB cellsPathogenic B cell subsetsPRL receptorsSLE-prone miceSystemic lupus erythematosusB cell numbersB cell subsetsB cell viabilityNormal B cellsExpression of Bcl2B cell survivalB-cell transformationLupus erythematosusLymphoproliferative diseaseAutocrine prolactinMouse modelPRLR isoformsMalignancyProlactinBCL2 expressionProlactin receptorIsoform-specific knockdownCell circuits between leukemic cells and mesenchymal stem cells block lymphopoiesis by activating lymphotoxin beta receptor signaling
Feng X, Sun R, Lee M, Chen X, Guo S, Geng H, Müschen M, Choi J, Pereira J. Cell circuits between leukemic cells and mesenchymal stem cells block lymphopoiesis by activating lymphotoxin beta receptor signaling. ELife 2023, 12: e83533. PMID: 36912771, PMCID: PMC10042536, DOI: 10.7554/elife.83533.Peer-Reviewed Original ResearchConceptsMesenchymal stem cellsLymphotoxin beta receptorLeukemic cellsBeta receptorsLeukemic cell growthBone marrow microenvironmentStem cellsTransplant recipientsAML cellsMyeloblastic leukemiaMouse modelBone marrowLeukemia growthLymphotoxin α1β2Marrow microenvironmentPharmacological disruptionLymphopoiesisReceptorsHematopoietic outputMolecular mechanismsErythropoiesisDNA damage response pathwayCell growthCellsPhysiological mechanisms
2020
IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells
Lee J, Robinson ME, Ma N, Artadji D, Ahmed MA, Xiao G, Sadras T, Deb G, Winchester J, Cosgun KN, Geng H, Chan LN, Kume K, Miettinen TP, Zhang Y, Nix MA, Klemm L, Chen CW, Chen J, Khairnar V, Wiita AP, Thomas-Tikhonenko A, Farzan M, Jung JU, Weinstock DM, Manalis SR, Diamond MS, Vaidehi N, Müschen M. IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells. Nature 2020, 588: 491-497. PMID: 33149299, PMCID: PMC8087162, DOI: 10.1038/s41586-020-2884-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CD19B-LymphocytesCell Transformation, NeoplasticFemaleGerminal CenterHumansIntegrinsMembrane MicrodomainsMembrane ProteinsMiceMice, Inbred C57BLMice, Inbred NODModels, MolecularPhosphatidylinositol 3-KinasesPhosphatidylinositol PhosphatesPhosphorylationReceptors, Antigen, B-CellRNA-Binding ProteinsSignal TransductionConceptsPI3KCell leukemiaAntiviral effector functionsAntigen-specific antibodiesInterferon-induced transmembrane proteinsIFITM3 functionDevelopment of leukemiaCell surfacePoor outcomeOncogenic PI3KClinical cohortEffector functionsGerminal centersMouse modelB cellsExpression of IFITM3Malignant transformationAccumulation of PIP3PI3K signalsCell receptorNormal numbersLeukemiaDefective expressionEndosomal proteinIFITM3
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 efficacyAutonomous 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
2016
Role of the transcription factor Ikaros in development of autoimmune disease
Schjerven H, Frietze S, Hai S, Hermiston M, Kogan S, Muschen M. Role of the transcription factor Ikaros in development of autoimmune disease. The Journal Of Immunology 2016, 196: 47.14-47.14. DOI: 10.4049/jimmunol.196.supp.47.14.Peer-Reviewed Original ResearchAnti-nuclear antibodiesAutoimmune diseasesB cellsB cell developmentSerum anti-nuclear antibodiesAuto-reactive B cellsReactive B cellsEx vivo analysisSpleen B cellsEx vivo studySecond signalBCR stimulationEarly B cell developmentRecent genome-wide association studiesVivo analysisMouse modelGenetic predispositionIkaros mutant miceTranscription factor IkarosMouse strainsDiseaseVivo studiesTargeted deletionZinc finger 1AutoimmunityPre-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
2015
Identification of BCL6 As a Therapeutic Target in RAS-Driven Acute Lymphoblastic Leukemia
Li Q, Hurtz C, Shojaee S, Chen Z, Geng H, Xiao G, Loh M, Ye B, Melnick A, Muschen M. Identification of BCL6 As a Therapeutic Target in RAS-Driven Acute Lymphoblastic Leukemia. Blood 2015, 126: 556. DOI: 10.1182/blood.v126.23.556.556.Peer-Reviewed Original ResearchTime of relapseAcute lymphoblastic leukemiaLymphoblastic leukemiaTherapeutic targetNOD/SCID miceInhibition of BCL6Conventional cytotoxic therapyBCL6 functionComplementary mouse modelsTransplant recipient miceTranscriptional repressor BCL6P53-dependent senescenceMEK inhibitor PD325901Patient-derived cellsInitial remissionTransplant recipientsLeukemia relapseInitial diagnosisPathway lesionsCytotoxic therapyRecipient miceSCID miceSame patientFatal leukemiaMouse modelErk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia
Shojaee S, Caeser R, Buchner M, Park E, Swaminathan S, Hurtz C, Geng H, Chan LN, Klemm L, Hofmann WK, Qiu YH, Zhang N, Coombes KR, Paietta E, Molkentin J, Koeffler HP, Willman CL, Hunger SP, Melnick A, Kornblau SM, Müschen M. Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia. Cancer Cell 2015, 28: 114-128. PMID: 26073130, PMCID: PMC4565502, DOI: 10.1016/j.ccell.2015.05.008.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Transformation, NeoplasticDNA-Binding ProteinsDual Specificity Phosphatase 6Host Cell Factor C1HumansIntracellular Signaling Peptides and ProteinsMAP Kinase Signaling SystemMembrane ProteinsMiceMice, TransgenicMolecular Sequence DataPrecursor Cell Lymphoblastic Leukemia-LymphomaPrognosisProtein Serine-Threonine KinasesSmall Molecule LibrariesTranscription FactorsConceptsAcute lymphoblastic leukemiaLymphoblastic leukemiaPatient-derived preNegative feedback regulationPre-B cell cloneCell deathImmediate cell deathMouse modelSmall molecule inhibitorsTherapeutic targetAcute activationMalignant transformationCell clonesFeedback regulationOncogenic signalingMolecule inhibitorsStrong activationLeukemiaDeathERKPre-B-cell transformationCell transformationActivationOncogenic transformationVast majority
2014
BCL6 Enables RAS-Mediated Pre-B Cell Transformation in Childhood Acute Lymphoblastic Leukemia
Hurtz C, Geng H, Xiao G, Loh M, Ye B, Melnick A, Muschen M. BCL6 Enables RAS-Mediated Pre-B Cell Transformation in Childhood Acute Lymphoblastic Leukemia. Blood 2014, 124: 3570. DOI: 10.1182/blood.v124.21.3570.3570.Peer-Reviewed Original ResearchDiffuse large B-cell lymphomaAcute lymphoblastic leukemiaLymphoblastic leukemiaMouse modelRas-ERK pathwayB-cell lineage leukemiaChildhood acute lymphoblastic leukemiaExpression levelsLarge B-cell lymphomaInhibition of BCL6Patient-derived preB cell lineage cellsBCL6 expressionConventional cytotoxic therapyNovel mouse modelBCL6 functionB-cell lymphomaGenetic mouse modelsMRNA expression levelsMEK inhibitor PD325901Lineage-specific deletionPre-B-cell transformationCell transformationInitial remissionQuantitative RT-PCRSelf-Enforcing Feedback Activation Between BCL6 and Tonic Pre-B Cell Receptor Signaling in Acute Lymphoblastic Leukemia
Geng H, Hurtz C, Baumjohann D, Chen Z, Chen W, Ballabio E, Xiao G, Lee J, Deucher A, Qi Z, Huang C, Nahar R, Kweon S, Shojaee S, Chan L, Yu J, Tyner J, Chang B, Kornblau S, Bijl J, Ye B, Paietta E, Melnick A, Roeder R, Hunger S, Loh M, Milne T, Muschen M. Self-Enforcing Feedback Activation Between BCL6 and Tonic Pre-B Cell Receptor Signaling in Acute Lymphoblastic Leukemia. Blood 2014, 124: 284. DOI: 10.1182/blood.v124.21.284.284.Peer-Reviewed Original ResearchPre-BCR expressionB cell receptorInhibition of BCL6Patient-derived preTreatment of patientsMature B-cell lymphomasB-cell lymphomaPre-BCR signalingTCF3-PBX1Cell lymphomaMouse modelCell receptorDeletion of Bcl6Time of diagnosisBCL6 expressionPoor clinical outcomeAcute lymphoblastic leukemiaNovel mouse modelFeedback activationTranscription factor Bcl6Genetic mouse modelsB cell precursorsInhibition of SykHeavy chain expressionLineage-specific deletion
2010
Targeting Survivin In Recalcitrant Acute Lymphoblastic Leukemia
Park E, Jiang E, Hsieh Y, Klemm L, Duy C, Conway E, Pelus L, Crispino J, Loh M, Kang E, Koo H, Yang A, Heisterkamp N, Kahn M, Muschen M, Kim Y. Targeting Survivin In Recalcitrant Acute Lymphoblastic Leukemia. Blood 2010, 116: 3263. DOI: 10.1182/blood.v116.21.3263.3263.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaMedian survival timeLymphoblastic leukemiaLong-term side effectsNucleic acid antisense oligonucleotideRelapse of leukemiaSurvivin shRNASingle-agent treatmentNew treatment modalitiesNOD/SCIDEvaluation of survivinInhibition of survivinCFU assayBone marrow cellsGFP controlFunction studiesKnockout mouse modelOverexpression of survivinAmgen IncLNA treatmentLeukemia relapseKnockdown of survivinTreatment modalitiesCurrent treatmentMouse model
2008
Obesity Accelerates T-Cell Leukemia in a Spontaneous Mouse Model.
Yun J, Klemm L, Behan J, Müschen M, Mittelman S. Obesity Accelerates T-Cell Leukemia in a Spontaneous Mouse Model. Blood 2008, 112: 1909. DOI: 10.1182/blood.v112.11.1909.1909.Peer-Reviewed Original ResearchAKR/J miceSpontaneous T cell leukemiaT-cell leukemiaT cell maturationDiet-induced obesityJ miceOnset of leukemiaLeukemic miceDiet groupMouse modelControl dietEffect of obesityCD4/CD8Non-obese counterpartsT cell subgroupsHigh-fat dietSpontaneous mouse modelMonths of ageT cell differentiationWeeks of ageTypes of cancerCD4/ CD8Clinical illnessThymus weightLifestyle parameters