2023
Cell 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
2019
Dynamic Assembly of a Feedback Complex to Regulate Oncogenic B-Cell Receptor-Signaling
Lee J, Kume K, Chen Z, Xiao G, Cosgun K, Chen L, Chan L, Klemm L, Chen C, Ma N, Chan W, Forman S, Zammarchi F, Van Berkel P, Melnick A, Ngo V, Geng H, Luger S, Litzow M, McManus M, Vaidehi N, Paietta E, Meffre E, Weinstock D, Müschen M. Dynamic Assembly of a Feedback Complex to Regulate Oncogenic B-Cell Receptor-Signaling. Blood 2019, 134: 393. DOI: 10.1182/blood-2019-131270.Peer-Reviewed Original ResearchB-cell malignanciesB-cell leukemiaB cell receptorPoor clinical outcomeTransplant recipientsB cellsCytoplasmic tailClinical outcomesADC therapeuticsFatal diseaseProximity-dependent biotin identificationRefractory B-cell malignanciesPatient-derived xenograft modelsT cell growth factorNormal B cell developmentClinical outcome dataShort cytoplasmic tailHomology-directed repairB-cell receptor signalingCell membrane translocationNF-κB activationInterleukin-2 (IL-2) functionB cell developmentB-cell tumorsGenetic mouse models
2018
Lgr5 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 miceCD25-Dependent Feedback Control of the B-Cell Receptor and Its Oncogenic Mimics in B-Cell Malignancies
Lee J, Kume K, Chen Z, Xiao G, Cosgun K, Chan L, Chen C, Pillai R, Chan W, Forman S, Kwak L, Zammarchi F, Van Berkel P, Weinstock D, Melnick A, Ngo V, Geng H, Luger S, Litzow M, Belot A, Uzel G, McManus M, Paietta E, Meffre E, Muschen M. CD25-Dependent Feedback Control of the B-Cell Receptor and Its Oncogenic Mimics in B-Cell Malignancies. Blood 2018, 132: 776. DOI: 10.1182/blood-2018-99-117553.Peer-Reviewed Original ResearchB cell receptorReceptor chainsB-cell malignanciesNormal B cell developmentT cell receptor signalingB-cell leukemiaHomology-directed repairCell membrane translocationPoor clinical outcomeB cell developmentFeedback regulatorTransplant recipientsNegative feedback regulatorNegative feedback regulationCytoplasmic tailClinical outcomesGene expressionMolecule downstreamCytokine receptor chainsBCR signalingT cellsB cell selectionGenetic mouse modelsProliferation signalsAstra Zeneca
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 model
2014
BACH2 promotes Lineage-Specific Fate Decisions in BCR-ABL1-Driven Leukemia
Park E, Swaminathan S, Sadiyah M, Igarashi K, Melnick A, Muschen M. BACH2 promotes Lineage-Specific Fate Decisions in BCR-ABL1-Driven Leukemia. Blood 2014, 124: 513. DOI: 10.1182/blood.v124.21.513.513.Peer-Reviewed Original ResearchLymphoid blast crisisFate decisionsB-cell lineageCML-like diseaseCell lineagesTumor suppressorCML cellsBCR-ABL1Transcription factorsTransplant recipientsLineage-specific transcription factorsChronic phaseB-cell-specific transcription factorCell-specific transcription factorsBlast crisisPre-B cell receptor checkpointB-cell lineage leukemiaPrimary human CML cellsRole of Bach2Multi-lineage progenitor cellsEmpty vector controlGene expression analysisSelective proliferative advantagePotent tumor suppressorCML chronic phaseIL2RA (CD25) Recruits Inhibitory Phosphatases to the Cell Membrane and Mediates Negative Feedback Control of STAT5 Signaling in Acute Lymphoblastic Leukemia
Geng H, Lee J, Chen Z, Masouleh B, Hurtz C, Park E, Xiao G, Parekh S, Kornblau S, Melnick A, Paietta E, Muschen M. IL2RA (CD25) Recruits Inhibitory Phosphatases to the Cell Membrane and Mediates Negative Feedback Control of STAT5 Signaling in Acute Lymphoblastic Leukemia. Blood 2014, 124: 788. DOI: 10.1182/blood.v124.21.788.788.Peer-Reviewed Original ResearchCD25 expressionB cell developmentClinical outcomesPoor overall clinical outcomeHuman prePatient-derived preHigh-risk subsetNegative feedback controlTime of diagnosisOverall clinical outcomePoor clinical outcomeHigh-risk subtypesLeukemia initiationAcute lymphoblastic leukemiaCell developmentPhosphorylation levelsImmune precipitationColony formation capacityTransplant recipientsTyrosine kinaseTransplant settingLymphoblastic leukemiaIL-2Cell surface expressionNormal B cell development
2011
BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia
Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM, Herzog S, Ramezani-Rad P, Jumaa H, Müller MC, Hofmann WK, Hochhaus A, Ye BH, Agarwal A, Druker BJ, Shah NP, Melnick AM, Müschen M. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. Journal Of Experimental Medicine 2011, 208: 2163-2174. PMID: 21911423, PMCID: PMC3201200, DOI: 10.1084/jem.20110304.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CD34BenzamidesCell SurvivalDisease Models, AnimalDNA-Binding ProteinsForkhead Transcription FactorsHematopoietic Stem CellsHumansImatinib MesylateLeukemia, Myelogenous, Chronic, BCR-ABL PositiveMiceMice, Inbred NODMice, KnockoutMice, SCIDNeoplasm TransplantationNeoplastic Stem CellsPiperazinesProtein Kinase InhibitorsProtein-Tyrosine KinasesProto-Oncogene Proteins c-bcl-6PyrimidinesTumor Cells, CulturedTumor Suppressor Protein p53ConceptsChronic myeloid leukemiaLeukemia-initiating cellsCML-initiating cellsTyrosine kinase inhibitorsTKI treatmentCML patientsMyeloid leukemiaCML cellsInhibition of BCL6Leukemia stem cell survivalLeukemia initiationHuman CML cellsColony formationBCR-ABL1 tyrosine kinaseInitiation of leukemiaTransplant recipientsBlast crisis transformationRepression of p53Pharmacological inhibitionStem cell survivalCML samplesLeukemiaClinical validationKinase inhibitorsBCL6