2023
Genetic Knockin Approaches to Reconstructing DLBCL-Subtypes from Human Germinal Center B-Cells
Khanduja D, Robinson M, Arce D, Klemm L, Leveille E, Kothari S, Caeser R, Hodson D, Müschen M. Genetic Knockin Approaches to Reconstructing DLBCL-Subtypes from Human Germinal Center B-Cells. Blood 2023, 142: 1627. DOI: 10.1182/blood-2023-190634.Peer-Reviewed Original ResearchSecondary lymphoid organsGerminal center B cellsMYD88 L265P mutationLymphoid organsLymph nodesB cellsL265P mutationHuman germinal center B cellsDLBCL subtypesNSG miceTonsillar germinal center B cellsLymphoma developmentPreclinical testingLymphoid tissue inducer cellsTransgenic expressionPoor clinical outcomeWild-type mutationsGenetic mouse modelsExon 5GC B cellsNBSGW miceClinical outcomesLTi cellsLymphoid folliclesInducer cells
2012
BACH2 Is Required for Pre-B Cell Receptor Checkpoint Control and p53-Dependent Tumor Surveillance
Swaminathan S, Kang H, Harvey R, Huang C, Buchner M, Chen Z, Geng H, Hall A, Igarashi K, Carroll W, Willman C, Melnick A, Muschen M. BACH2 Is Required for Pre-B Cell Receptor Checkpoint Control and p53-Dependent Tumor Surveillance. Blood 2012, 120: 1300. DOI: 10.1182/blood.v120.21.1300.1300.Peer-Reviewed Original ResearchFavorable clinical outcomeTyrosine kinase inhibitorsPre-B cell cloneOncogene-induced senescenceClinical outcomesLeukemia cellsB cellsBCR-ABL1Multivariate analysisCell clonesAcute lymphoblastic leukemia cellsTime of diagnosisMRNA levelsTumor suppressor CDKN2AGerminal center B cellsLymphoblastic leukemia cellsEvidence of MRDNormal human bone marrowCases of childhoodSigns of diseaseRelapse of childhoodBACH2 locusImmunoglobulin heavy chain geneQuantitative RT-PCRMYC results
2011
BACH2 Mediates Early B Cell Differentiation and Oncogene-Induced Senescence in Acute Lymphoblastic Leukemia
Swaminathan S, Huang C, Titz B, Buchner M, Geng H, Graeber T, Willman C, Igarashi K, Melnick A, Muschen M. BACH2 Mediates Early B Cell Differentiation and Oncogene-Induced Senescence in Acute Lymphoblastic Leukemia. Blood 2011, 118: 562. DOI: 10.1182/blood.v118.21.562.562.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsRelapse of childhoodBCR-ABL1B cell differentiationDay 29Leukemia cellsB cellsMRNA levelsOverexpression of MYCEarly B cell differentiationAcute lymphoblastic leukemia cellsAcute lymphoblastic leukemiaTumor suppressor CDKN2AGerminal center B cellsLymphoblastic leukemia cellsEvidence of MRDNormal human bone marrowSigns of diseaseCommon gene expression signatureFraction of casesPositive MRDQuantitative RT-PCRRole of Bach2Gene expression signaturesImatinib treatment
2009
Activation-Induced Cytidine Deaminase Accelerates Clonal Evolution of BCR-ABL1-Driven B Cell Lineage Acute Lymphoblastic Leukemia.
Gruber T, Chang M, Sposto R, Müschen M. Activation-Induced Cytidine Deaminase Accelerates Clonal Evolution of BCR-ABL1-Driven B Cell Lineage Acute Lymphoblastic Leukemia. Blood 2009, 114: 181. DOI: 10.1182/blood.v114.22.181.181.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaAberrant AID expressionBCR-ABL1Lymphoblastic leukemiaB cellsBCR-ABL1 kinase domain mutationsB-cell lineage acute lymphoblastic leukemiaClonal evolutionTumor suppressor geneAberrant somatic hypermutationAID expressionB-cell lymphomaKinase domain mutationsGerminal center B cellsBone marrow cellsSuppressor geneBCR-ABL1 kinaseGC B cellsHazard ratioMedian survivalGenetic instabilityImatinib treatmentSomatic hypermutationB-cell lymphomagenesisCell lymphomaBCL6 Is Required for Leukemia-Initiation and Self-Renewal Signaling in Chronic Myeloid Leukemia.
Hurtz C, Duy C, Cerchietti L, Park E, Ci W, Swaminathan S, Kweon S, Klemm L, Kim Y, Martinelli G, Hofmann W, Ye B, Melnick A, Müschen M. BCL6 Is Required for Leukemia-Initiation and Self-Renewal Signaling in Chronic Myeloid Leukemia. Blood 2009, 114: 2167. DOI: 10.1182/blood.v114.22.2167.2167.Peer-Reviewed Original ResearchDiffuse large B-cell lymphomaHuman CML cellsCML cellsB cellsGC B cellsImatinib treatmentBCR-ABL1Large B-cell lymphomaInhibition of BCL6Chronic myeloid leukemiaBCL6 functionNovel therapeutic approachesB-cell lymphomaGerminal center B cellsTranscriptional repressor BCL6Myeloid progenitor cellsBCR-ABL1 kinaseImatinib resultsRole of BCL6Cell cycle arrestMyeloid leukemiaNovel peptide inhibitorTherapeutic approachesBone marrowProtein upregulation
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 miceLymphoid 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
The Balance between Myc and Bcl6 Determines Self-Renewal or Differentiation of Pre-B Cells.
Duy C, de Alboran I, Jumaa H, Muschen M. The Balance between Myc and Bcl6 Determines Self-Renewal or Differentiation of Pre-B Cells. Blood 2007, 110: 797. DOI: 10.1182/blood.v110.11.797.797.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaBCR-ABL1B cellsDownregulation of MYCImmature B cellsEarly B cell developmentB cell differentiationLymphoblastic leukemiaExpression of MYCB cell developmentNovo expressionLarge B-cell lymphomaBCR-ABL1 inhibitorsB-cell lymphomaGerminal center B cellsB-cell malignanciesDe novo expressionCell lymphomaBone marrowPre-B cell culturesPre B cellsLeukemic transformationInduction of differentiationIL7Expression of BCL6Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1–transformed acute lymphoblastic leukemia cells
Feldhahn N, Henke N, Melchior K, Duy C, Soh BN, Klein F, von Levetzow G, Giebel B, Li A, Hofmann WK, Jumaa H, Müschen M. Activation-induced cytidine deaminase acts as a mutator in BCR-ABL1–transformed acute lymphoblastic leukemia cells. Journal Of Experimental Medicine 2007, 204: 1157-1166. PMID: 17485517, PMCID: PMC2118573, DOI: 10.1084/jem.20062662.Peer-Reviewed Original ResearchMeSH KeywordsB-LymphocytesBase SequenceBlotting, WesternCytidine DeaminaseDNA Mutational AnalysisDNA-Binding ProteinsFlow CytometryFusion Proteins, bcr-ablGene Expression Regulation, NeoplasticGenes, mycHumansImmunoglobulin Variable RegionMolecular Sequence DataMutationOligonucleotide Array Sequence AnalysisOligonucleotidesPhiladelphia ChromosomePrecursor Cell Lymphoblastic Leukemia-LymphomaProtein-Tyrosine KinasesProto-Oncogene Proteins c-bcl-6Reverse Transcriptase Polymerase Chain ReactionRNA InterferenceSequence AlignmentConceptsAcute lymphoblastic leukemiaBCR-ABL1BCR-ABL1 kinaseUnfavorable prognosisActivation-induced cytidine deaminaseAcute lymphoblastic leukemia cellsAID expressionAberrant AID expressionBCR-ABL1 kinase activityIgH V region genesTumor suppressor gene CDKN2BGerminal center B cellsLymphoblastic leukemia cellsB cell precursorsImmunoglobulin heavy chain variable region genesLymphoblastic leukemiaLeukemia subsetsB cellsDNA single-strand breaksPH casesPhiladelphia chromosomeHeavy chain variable region genesAberrant expressionCell precursorsChain variable region genes
2001
Molecular Single-Cell Analysis of Hodgkin- and Reed-Sternberg Cells Harboring Unmutated Immunoglobulin Variable Region Genes
Müschen M, Küppers R, Spieker T, Bräuninger A, Rajewsky K, Hansmann M. Molecular Single-Cell Analysis of Hodgkin- and Reed-Sternberg Cells Harboring Unmutated Immunoglobulin Variable Region Genes. Laboratory Investigation 2001, 81: 289-295. PMID: 11310822, DOI: 10.1038/labinvest.3780237.Peer-Reviewed Original ResearchConceptsImmunoglobulin variable region genesRegion genesVariable region genesGerminal center B cellsSomatic mutationsFounder cellsGerminal center founder cellsB cellsGenesIntrinsic propensityClonal progenyUnmutated immunoglobulin variable region genesClassical Hodgkin's diseaseAntigen-experienced B cellsCell analysisRS cellsMutationsNaive B cellsReed-Sternberg cellsCellsB-lineageLineagesProgenyClonesApoptosisOct-2 and Bob-1 deficiency in Hodgkin and Reed Sternberg cells.
Re D, Müschen M, Ahmadi T, Wickenhauser C, Staratschek-Jox A, Holtick U, Diehl V, Wolf J. Oct-2 and Bob-1 deficiency in Hodgkin and Reed Sternberg cells. Cancer Research 2001, 61: 2080-4. PMID: 11280769.Peer-Reviewed Original ResearchConceptsImmunoglobulin gene expressionH-RS cellsGene expressionOct-2 transcriptsOct-2 proteinTranscription factor Oct-2Primary H-RS cellsCell linesTranscription machineryBob-1Gene deregulationOctamer siteHodgkin's disease-derived cell linesImmunoglobulin genesNovel mechanismGerminal center B cellsCrippling mutationsClassical Hodgkin's diseaseProtein expressionB cellsTranscriptsExpressionProteinReed-Sternberg cellsCells
2000
Somatic Mutation of the Cd95 Gene in Human B Cells as a Side-Effect of the Germinal Center Reaction
Müschen M, Re D, Jungnickel B, Diehl V, Rajewsky K, Küppers R. Somatic Mutation of the Cd95 Gene in Human B Cells as a Side-Effect of the Germinal Center Reaction. Journal Of Experimental Medicine 2000, 192: 1833-1840. PMID: 11120779, PMCID: PMC2213498, DOI: 10.1084/jem.192.12.1833.Peer-Reviewed Original ResearchConceptsDeath domainCD95 geneSomatic mutationsNegative selectionNon-Ig genesHuman B cellsSomatic hypermutation machineryApoptosis-resistant cellsTumor suppressor geneDD mutationsLast exonHypermutation machinerySuppressor geneApoptosis resistanceGenesB cellsImmunoglobulin genesGerminal center B cellsSomatic hypermutationMutationsCD95 pathwayGC B-cell lymphomasGC B cellsCellsGerminal center reaction