2021
Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer
Sadras T, Martin M, Kume K, Robinson ME, Saravanakumar S, Lenz G, Chen Z, Song JY, Siddiqi T, Oksa L, Knapp AM, Cutler J, Cosgun KN, Klemm L, Ecker V, Winchester J, Ghergus D, Soulas-Sprauel P, Kiefer F, Heisterkamp N, Pandey A, Ngo V, Wang L, Jumaa H, Buchner M, Ruland J, Chan WC, Meffre E, Martin T, Müschen M. Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer. Molecular Cell 2021, 81: 2094-2111.e9. PMID: 33878293, PMCID: PMC8239336, DOI: 10.1016/j.molcel.2021.03.043.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CD19AutoimmunityB-LymphocytesCalciumCell DifferentiationCell Transformation, NeoplasticEnzyme ActivationHumansImmune ToleranceLymphoma, B-CellMiceModels, GeneticNeoplasm ProteinsNeoplasmsNFATC Transcription FactorsPhosphatidylinositol 3-KinasesProtein BindingReceptors, Antigen, B-CellSignal TransductionSyk KinaseZAP-70 Protein-Tyrosine KinasePON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis
Pan L, Hong C, Chan LN, Xiao G, Malvi P, Robinson ME, Geng H, Reddy ST, Lee J, Khairnar V, Cosgun KN, Xu L, Kume K, Sadras T, Wang S, Wajapeyee N, Müschen M. PON2 subverts metabolic gatekeeper functions in B cells to promote leukemogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2016553118. PMID: 33531346, PMCID: PMC7896313, DOI: 10.1073/pnas.2016553118.Peer-Reviewed Original ResearchConceptsTransplant recipient miceDNA double-strand breaksNormal B cell developmentDouble-strand breaksB cell developmentGenetic deletionB cellsLymphoid transcription factorsGlucose transporter GLUT1Gatekeeper functionGlucose uptakeRecipient miceTranscription factorsSomatic recombinationSynthetic lethalityB-cell acute lymphoblastic leukemiaCell developmentMetabolic gatekeeperRefractory B-ALLDeficient murineCell acute lymphoblastic leukemiaPoor clinical outcomeCell typesAcute lymphoblastic leukemiaGlucose transport
2019
MicroRNA-142 Is an Essential Negative Regulator of B Cell Maturation and Malignant Transformation
Graham N, Wang W, Magilnick N, Lee J, Wang H, Zhang B, Marcucci G, Muschen M, Reyes E, Boldin M. MicroRNA-142 Is an Essential Negative Regulator of B Cell Maturation and Malignant Transformation. The Journal Of Immunology 2019, 202: 53.22-53.22. DOI: 10.4049/jimmunol.202.supp.53.22.Peer-Reviewed Original ResearchMalignant B-cell transformationB cell developmentEμ-myc transgenic miceEssential negative regulatorB cell maturationNegative regulatorB-cell transformationMiR-142Transgenic miceCell developmentCell transformationB-cell lymphoblastic leukemiaCell maturationEarly B cell developmentPrimary B cell developmentEarly B cell progenitorsPre-B cell stageMature B cell compartmentB cell compartmentB cell progenitorsB-cell ontogenesisIL-7 stimulationImmature B cellsLymphoblastic leukemiaCell ontogenesis
2017
PON2 Exemplifies a Unique Dependency of B Cell Lineage ALL Cells on Detoxifying Lactonases
Xiao G, Hong C, Geng H, Muschen M. PON2 Exemplifies a Unique Dependency of B Cell Lineage ALL Cells on Detoxifying Lactonases. Blood 2017, 130: 882. DOI: 10.1182/blood.v130.suppl_1.882.882.Peer-Reviewed Original ResearchPatient-derived preB-cell lineageParaoxonase 2BCR-ABL1PON2 expressionB cell developmentB-lineageExpression levelsAdult clinical trialsPON2-deficient miceTime of diagnosisPoor clinical outcomeMRNA levelsBone marrow B cell precursorsSpecific treatment requirementsLactone metabolitesMultiple fetal tissuesG0/G1 phaseB cell precursorsNormal B cellsCell lineagesNormal hematopoietic cellsCell developmentPON2 deficiencyQuantitative RT-PCR
2015
CD25 (IL2RA) Orchestrates Negative Feedback Control and Stabilizes Oncogenic Signaling Strength in Acute Lymphoblastic Leukemia
Lee J, Chen Z, Geng H, Xiao G, Eugene P, Parekh S, Kornblau S, Melnick A, Abbas A, Paietta E, Muschen M. CD25 (IL2RA) Orchestrates Negative Feedback Control and Stabilizes Oncogenic Signaling Strength in Acute Lymphoblastic Leukemia. Blood 2015, 126: 1434. DOI: 10.1182/blood.v126.23.1434.1434.Peer-Reviewed Original ResearchPre-BCR signalingPre-B cell receptorCytoplasmic tailOncogenic tyrosine kinasesB cell developmentTyrosine kinaseSerine/threonine protein kinaseCell developmentConstitutive membrane localizationCytoplasmic interaction partnersReceptor chainsEarly B cell developmentThreonine protein kinaseDownstream tyrosine kinasePre-B cell stageShort cytoplasmic tailNegative feedback controlComprehensive gene expression analysisDependent signal transductionTyrosine kinase BtkTyrosine kinase oncogenesGene expression analysisSerial transplantation experimentsB lineage cellsAbsence of CD25STAT5 antagonism of B cell superenhancer networks initiates progenitor B cell leukemia and predicts patient survival (HEM1P.222)
Farrar M, Katerndahl C, Heltemes Harris L, Willette M, Henzler C, Yang R, Silverstein K, Frietze S, Schjerven H, Ramsey L, Hubbard G, Muschen M, Kornblau S. STAT5 antagonism of B cell superenhancer networks initiates progenitor B cell leukemia and predicts patient survival (HEM1P.222). The Journal Of Immunology 2015, 194: 50.5-50.5. DOI: 10.4049/jimmunol.194.supp.50.5.Peer-Reviewed Original ResearchB cell developmentPatient outcomesB cellsB-cell acute lymphoblastic leukemiaProgenitor B cellsCell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaCell developmentDirect clinical relevanceB-cell leukemiaShort remissionsAggressive diseasePatient survivalLymphoblastic leukemiaTranscription factor STAT5Cell leukemiaClinical relevanceTranscriptional programsLeukemiaDegree of antagonismPre-BCRSurvivalSTAT5 activationMicroarray analysisSTAT5
2014
Divergent Lineage-Specific Functions of PP2A in Chronic Phase CML and Lymphoid Blast Crisis
Xiao G, Geng H, Chan L, Chen Z, Muschen M. Divergent Lineage-Specific Functions of PP2A in Chronic Phase CML and Lymphoid Blast Crisis. Blood 2014, 124: 3128. DOI: 10.1182/blood.v124.21.3128.3128.Peer-Reviewed Original ResearchFunction of PP2ACell lineagesB cell developmentB-cell lineageSer/Thr phosphataseCell developmentPI3K-AktEarly B cell developmentProtein phosphatase 2ALineage-specific functionsNormal B cell developmentChronic phase chronic myeloid leukemiaLineage-specific requirementGlycolytic fluxPre-B cell receptor checkpointMyeloid lineagePhase chronic myeloid leukemiaChronic myeloid leukemiaRegulation of AktS6 ribosomal proteinHigh glycolytic fluxRapid cell deathLymphoid blast crisisImportant tumor suppressorColony formation capabilityIL2RA (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 developmentFOXM1 Mediates Drug-Resistance and Represents a Therapeutic Target in Pre-B Acute Lymphoblastic Leukemia
Buchner M, Park E, Klemm L, Geng H, Kopanja D, Raychaudhuri P, Muschen M. FOXM1 Mediates Drug-Resistance and Represents a Therapeutic Target in Pre-B Acute Lymphoblastic Leukemia. Blood 2014, 124: 790. DOI: 10.1182/blood.v124.21.790.790.Peer-Reviewed Original ResearchB cell developmentFOXM1 protein levelsAcute lymphoblastic leukemiaB cell progenitorsB cell precursorsCell developmentFOXO factorsRegulation of FoxM1BCR-ABL1Cell lineagesB-cell lineageBox transcription factor familyCell progenitorsProtein levelsEarly B cell developmentLymphoblastic leukemiaTranscription factor familyCell precursorsGene expression surveyFoxM1 downregulationNormal B cell developmentPre-B cell receptor checkpointFOXM1 expressionTherapeutic targetB cells
2013
BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint
Swaminathan S, Huang C, Geng H, Chen Z, Harvey R, Kang H, Ng C, Titz B, Hurtz C, Sadiyah MF, Nowak D, Thoennissen GB, Rand V, Graeber TG, Koeffler HP, Carroll WL, Willman CL, Hall AG, Igarashi K, Melnick A, Müschen M. BACH2 mediates negative selection and p53-dependent tumor suppression at the pre-B cell receptor checkpoint. Nature Medicine 2013, 19: 1014-1022. PMID: 23852341, PMCID: PMC3954721, DOI: 10.1038/nm.3247.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBasic-Leucine Zipper Transcription FactorsCell DeathCell DifferentiationCell SurvivalCell Transformation, NeoplasticDNA-Binding ProteinsGene DeletionGene Expression Regulation, LeukemicGreen Fluorescent ProteinsImmunoglobulin mu-ChainsMiceMolecular Sequence DataPAX5 Transcription FactorPre-B Cell ReceptorsPrecursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidProto-Oncogene Proteins c-bcl-6Proto-Oncogene Proteins c-mycRNA, MessengerSTAT5 Transcription FactorTreatment OutcomeTumor Suppressor Protein p53V(D)J Recombination
2010
Dominant-Negative Impact of PAX5/TEL on Downstream Targets of PAX5 and Essential Pre-B Cell Receptor Genes
Iwanski G, Thoennissen N, Nakitandwe J, Lin P, Kawamata N, Nahar R, Ramezani-Rad P, Chen S, Shurtleff S, Nowak D, Ruckert C, Dugas M, Bokemeyer C, Fazio G, Biondi A, Cazzaniga G, Downing J, Müschen M, Koeffler H. Dominant-Negative Impact of PAX5/TEL on Downstream Targets of PAX5 and Essential Pre-B Cell Receptor Genes. Blood 2010, 116: 3231. DOI: 10.1182/blood.v116.21.3231.3231.Peer-Reviewed Original ResearchB cell developmentPre-BCR signalingDominant-negative impactCell developmentTarget genesReporter constructsTyrosine kinasePre-B cell receptorPax5 target genesWild-type PAX5CCAAT/enhancer binding protein alphaBruton's agammaglobulinemia tyrosine kinaseTranscription factor Pax5Downstream target genesGene expression profilesDominant negative roleBCR pathwayGene expression dataLuciferase reporter constructsEndogenous Pax5High expression levelsTranscriptional activationAffymetrix HG-U133Downstream genesExpression of PAX5
2009
BCL6 Is Critical for the Development of a Diverse Primary B Cell Repertoire.
Duy C, Yu J, Swaminathan S, Nahar R, Kweon S, Polo J, Valls E, Klemm L, Cerchietti L, von Levetzow G, Herzog S, Jumaa H, de Alborán I, Melnick A, Ye B, Müschen M. BCL6 Is Critical for the Development of a Diverse Primary B Cell Repertoire. Blood 2009, 114: 91. DOI: 10.1182/blood.v114.22.91.91.Peer-Reviewed Original ResearchB cell developmentDNA damage stressTranscriptional repressionCell developmentPrimary B-cell repertoireBCL6 functionB cell precursorsDNA damage-induced apoptosisDNA damage response pathwayActive STAT5 mutantDNA damageEarly B cell developmentB cell repertoireNormal B cell developmentDamage response pathwayDamage-induced apoptosisEarly B cell differentiationGene expression patternsCell precursorsPre-B cell populationsSelf-renewal defectGene expression analysisDamage stressSimilar expression levelsEarly B-cell precursors