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
2016
Transcriptional Control of Glucose and Energy Supply Prevents Oncogenic Signaling and B Cell Transformation
Chan L, Chen Z, Xiao G, Lee J, Geng H, Christian H, Cazzaniga V, Cazzaniga G, Dickins R, Müschen M. Transcriptional Control of Glucose and Energy Supply Prevents Oncogenic Signaling and B Cell Transformation. Blood 2016, 128: 437. DOI: 10.1182/blood.v128.22.437.437.Peer-Reviewed Original ResearchB-cell transcription factorsTranscription factorsCellular ATP levelsPositive regulatorOncogenic signalingNegative regulatorSurvival fitnessCRISPR/Cas9-mediated deletionWild-type PAX5Glucose uptakeQuantitative chromatin immunoprecipitationEffect of PAX5Regions of genesB cell identityProtein levelsCompetitive growth assaysATP levelsTumor suppressive functionSecondary genetic lesionsB-lineageChIPseq dataTranscriptional controlChromatin immunoprecipitationB-cell transformationPatient-derived preBCOR regulates myeloid cell proliferation and differentiation
Cao Q, Gearhart M, Gery S, Shojaee S, Yang H, Sun H, Lin D, Bai J, Mead M, Zhao Z, Chen Q, Chien W, Alkan S, Alpermann T, Haferlach T, Müschen M, Bardwell V, Koeffler H. BCOR regulates myeloid cell proliferation and differentiation. Leukemia 2016, 30: 1155-1165. PMID: 26847029, PMCID: PMC5131645, DOI: 10.1038/leu.2016.2.Peer-Reviewed Original ResearchConceptsMyeloid cell proliferationHox genesCell proliferationFunction mutationsUbiquitin ligase subunitRNA expression profilingPolycomb groupEnhanced cell proliferationOverexpression allelesHOXA genesExpression profilingGene expressionConditional lossMyeloid differentiationMurine cellsFamily complexesNormal hematopoiesisGenesBone marrow cellsBCOR expressionProtein levelsMechanistic explanationDifferentiation rateAML patient samplesMutations
2014
FOXM1 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
Identification Of BCL6 As a Therapeutic Target In MLL-Rearranged ALL
Hurtz C, Geng H, Ballabio E, Xiao G, Ng C, Masouleh B, Willman C, Armstrong S, Milne T, Melnick A, Muschen M. Identification Of BCL6 As a Therapeutic Target In MLL-Rearranged ALL. Blood 2013, 122: 72. DOI: 10.1182/blood.v122.21.72.72.Peer-Reviewed Original ResearchDiffuse large B-cell lymphomaFunction of Bcl6White blood countPoor clinical outcomeAcute lymphoblastic leukemiaMinimal residual diseaseClinical outcomesMLL-AF4Clinical trialsBCL6 levelsPositive minimal residual diseasePharmacological inhibitionHigher white blood countExpression levelsLarge B-cell lymphomaAberrant expressionChemotherapy drugs vincristineBCL6 protein levelsTime of diagnosisWorse clinical outcomesBCL6 expressionRelapse-free survivalProtein levelsPediatric clinical trialsB-cell lymphoma
2012
Targeting BCL6-Mediated Drug-Resistance in High-Risk Childhood ALL
Hurtz C, Ramezani-Rad P, Geng H, Kharabi B, Carroll W, Willman C, Armstrong S, Melnick A, Muschen M. Targeting BCL6-Mediated Drug-Resistance in High-Risk Childhood ALL. Blood 2012, 120: 776. DOI: 10.1182/blood.v120.21.776.776.Peer-Reviewed Original ResearchDiffuse large B-cell lymphomaMLL-AF4High expression levelsBCL6 expressionExpression levelsB-cell lineage leukemiaHigh-risk childhood leukemiaMinimal residual disease statusNOD/SCID miceLarge B-cell lymphomaAberrant expressionFunction of Bcl6High-risk childhoodOnset of chemotherapyResidual disease statusTime of diagnosisPoor clinical outcomeProtein levelsBCR-ABL1 kinase activityB-cell lymphomaHigh-risk regimenBone marrow precursor cellsTransplant recipient miceGenetic mouse modelsB cell precursors
2011
DUSP6-Mediated Negative Feedback to Oncogenic Tyrosine Kinase Signaling Prevents Excessive Accumulation of ROS and Enables Leukemia Cell Survival
Shojaee S, Buchner M, Geng H, Melnick A, Gery S, Molkentin J, Koeffler P, Muschen M. DUSP6-Mediated Negative Feedback to Oncogenic Tyrosine Kinase Signaling Prevents Excessive Accumulation of ROS and Enables Leukemia Cell Survival. Blood 2011, 118: 1479. DOI: 10.1182/blood.v118.21.1479.1479.Peer-Reviewed Original ResearchCellular senescenceEffects of BCIProtein levelsCpG methylation analysisLeukemia cellsOncogene-induced senescenceGene expression changesLineage leukemiaCpG methylation levelsOncogenic tyrosine kinasesPharmacological inhibitionTyrosine kinase activityActivation of p53Small molecule inhibitorsBone marrow progenitor cellsGenetic experimentsDUSP6 functionLeukemia cell survivalTherapeutic targetB-cell lymphoma cell linesMarrow progenitor cellsNormal growth kineticsHigh ROS levelsKinase activityPromoter region
2010
BCL6 Is Required for the Maintenance of Leukemia-Initiating Cells In Chronic Myeloid Leukemia
Hurtz C, Duy C, Cerchietti L, Chatzi K, Park E, Klemm L, Kim Y, Kahn M, Braig M, Muller M, Hochhaus A, Ye B, Melnick A, Muschen M. BCL6 Is Required for the Maintenance of Leukemia-Initiating Cells In Chronic Myeloid Leukemia. Blood 2010, 116: 202. DOI: 10.1182/blood.v116.21.202.202.Peer-Reviewed Original ResearchDiffuse large B-cell lymphomaNOD/SCID miceChronic myeloid leukemiaHuman CML cellsLeukemia stem cellsTyrosine kinase inhibitorsCML cellsLeukemia-initiating cellsSCID miceMyeloid leukemiaCML patientsBCL6 expressionLeukemia stem cell maintenanceLSK cellsLarge B-cell lymphomaAbsence of Bcl6CML-initiating cellsCML-like leukemiaDistinct side populationStem cellsProtein levelsColony formationGene expression changesB-cell lymphomaLeukemia initiating cells
2008
BCL6-Mediated Survival Signaling Promotes Drug-Resistance in BCRABL1- Driven Acute Lymphoblastic Leukemia
Duy C, Yu J, Cerchietti L, Klemm L, Nahar R, Kim Y, Heisterkamp N, Martinelli G, Hofmann W, Jumaa H, Melnick A, Ye B, Muschen M. BCL6-Mediated Survival Signaling Promotes Drug-Resistance in BCRABL1- Driven Acute Lymphoblastic Leukemia. Blood 2008, 112: 295. DOI: 10.1182/blood.v112.11.295.295.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaGerminal center B cellsImatinib treatmentBCR-ABL1Bone marrowB cellsLymphoblastic leukemiaHuman BCR-ABL1NOD/SCID miceFunction of Bcl6Inhibition of BCL6Low-dose imatinibBCL6 expressionLeukemia cellsP53 signalingProtein levelsCombination of imatinibGerminal center B cell survivalTail vein injectionNovel treatment conceptsTranscriptional repressor BCL6B cell survivalLow proliferation rateRecipient miceSCID mice
1998
Regulation of CD95 (Apo-1/Fas) Ligand and Receptor Expression in Human Embryonal Carcinoma Cells by Interferon γ and all-trans Retinoic Acid
Müschen M, Warskulat U, Schmidt B, Schulz W, Häussinger D. Regulation of CD95 (Apo-1/Fas) Ligand and Receptor Expression in Human Embryonal Carcinoma Cells by Interferon γ and all-trans Retinoic Acid. Biological Chemistry 1998, 379: 1083-1092. PMID: 9792441, DOI: 10.1515/bchm.1998.379.8-9.1083.Peer-Reviewed Original ResearchConceptsTrans retinoic acidTera-2 cellsTera-2 embryonal carcinoma cellsEmbryonal carcinoma cellsRetinoic acidT lymphocytesCarcinoma cellsJurkat T lymphocytesCD95 ligandReceptor isoformsCD95 receptorCD95 ligand expressionHuman embryonal carcinoma cellsAntitumor immunityControl conditionReceptor expressionInterferon γInterferon gammaLigand expressionProtein levelsDifferential regulationCD95 ligationIFNgammaLymphocytesApoptosis