2019
Targeting Unique Synthetic Lethal Interactions between PI3K and MYC in B-ALL
Xiao G, Kume K, Geng H, Han T, Klemm L, Müschen M. Targeting Unique Synthetic Lethal Interactions between PI3K and MYC in B-ALL. Blood 2019, 134: 3785. DOI: 10.1182/blood-2019-128719.Peer-Reviewed Original ResearchMYC protein levelsPI3KCell deathMYC overexpressionPTEN deletionRescue effectProtein levelsPI3K hyperactivationMYC protein stabilityTranscription factor Pax5Wild-type MycDegradation of MycSynthetic lethal interactionsGlutamine consumptionGene expression profilesCellular ATP levelsInhibition of glutaminolysisATP levelsPTEN inhibitor SF1670Deletion of PTENMyc mutantsPI3K pathwayPI3K subunitsMyc proteinProtein gene
2018
B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies
Xiao G, Chan LN, Klemm L, Braas D, Chen Z, Geng H, Zhang QC, Aghajanirefah A, Cosgun KN, Sadras T, Lee J, Mirzapoiazova T, Salgia R, Ernst T, Hochhaus A, Jumaa H, Jiang X, Weinstock DM, Graeber TG, Müschen M. B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies. Cell 2018, 173: 470-484.e18. PMID: 29551267, PMCID: PMC6284818, DOI: 10.1016/j.cell.2018.02.048.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesCarbonCell Line, TumorCell SurvivalGlucoseGlucosephosphate DehydrogenaseGlycolysisHumansIkaros Transcription FactorMiceMice, Inbred C57BLMice, Inbred NODOxidative StressPAX5 Transcription FactorPentose Phosphate PathwayPrecursor Cell Lymphoblastic Leukemia-LymphomaProtein Phosphatase 2Proto-Oncogene Proteins c-bcl-2Transcription, GeneticConceptsPentose phosphate pathwayCarbon utilizationSerine/threonine protein phosphatase 2AB-cell transcription factor PAX5Transcription factor Pax5Favor of glycolysisSmall molecule inhibitionPhosphatase 2ATranscriptional repressionRedox homeostasisOncogenic transformationTumor suppressorMolecule inhibitionPP2AGenetic studiesPhosphate pathwayB cell activationEssential roleB-cell malignanciesCell malignanciesB cellsAntioxidant protectionOxidative stressB-cell tumorsCell activation
2017
Metabolic gatekeeper function of B-lymphoid transcription factors
Chan LN, Chen Z, Braas D, Lee JW, Xiao G, Geng H, Cosgun KN, Hurtz C, Shojaee S, Cazzaniga V, Schjerven H, Ernst T, Hochhaus A, Kornblau SM, Konopleva M, Pufall MA, Cazzaniga G, Liu GJ, Milne TA, Koeffler HP, Ross TS, Sánchez-García I, Borkhardt A, Yamamoto KR, Dickins RA, Graeber TG, Müschen M. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 2017, 542: 479-483. PMID: 28192788, PMCID: PMC5621518, DOI: 10.1038/nature21076.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesAnimalsB-LymphocytesCarcinogenesisCarrier ProteinsCell DeathChromatin ImmunoprecipitationCitric Acid CycleDisease Models, AnimalEnergy MetabolismFemaleGene Expression Regulation, NeoplasticGlucocorticoidsGlucoseHumansIkaros Transcription FactorMiceMice, TransgenicPAX5 Transcription FactorPrecursor B-Cell Lymphoblastic Leukemia-LymphomaProtein Serine-Threonine KinasesPyruvic AcidReceptor, Cannabinoid, CB2Receptors, GlucocorticoidSequence Analysis, RNATranscription FactorsConceptsB cellsLeukemia B cellsSupply of glucoseTranscription factor Pax5Tumor suppressorGatekeeper functionCellsTranscription factorsTherapyIKZF1
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
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 lesions
2008
Lymphoid Blast Crisis Transformation and Development of Drug- Resistance in Chronic Myeloid Leukemia Are Driven by Aberrant Somatic Hypermutation
Klemm L, Duy C, Feldhahn N, Groffen J, Kim Y, Hofmann W, Jumaa H, Lieber M, Casellas R, Muschen M. Lymphoid Blast Crisis Transformation and Development of Drug- Resistance in Chronic Myeloid Leukemia Are Driven by Aberrant Somatic Hypermutation. Blood 2008, 112: 571. DOI: 10.1182/blood.v112.11.571.571.Peer-Reviewed Original ResearchChronic phase chronic myeloid leukemiaPhase chronic myeloid leukemiaChronic myeloid leukemiaLymphoid blast crisisGerminal center B cellsAberrant somatic hypermutationSomatic hypermutationBCR-ABL1 kinase domainKinase domainEctopic expressionB cell lineage commitmentB-cell-specific transcription factor Pax5Lineage-specific activationCML cellsAID protein levelsImatinib resistanceAberrant activationB cellsTranscription factor Pax5AID expressionBCR-ABL1Cell lineage commitmentCytidine deaminase AIDDownstream regulatory elementsB-cell-specific activation
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