2023
Optogenetic Control of Oncogenic Signaling in B-Cell Malignancies
Kume K, Lee J, Cheng Z, Robinson M, Leveille E, Cosgun K, Chan L, Feng Y, Arce D, Khanduja D, Toomre D, Müschen M. Optogenetic Control of Oncogenic Signaling in B-Cell Malignancies. Blood 2023, 142: 4138. DOI: 10.1182/blood-2023-190926.Peer-Reviewed Original ResearchB-cell malignanciesB-cell lymphomaMature B-cell lymphomasB cell deathB cellsB cell developmentGenetic deletionMantle cell lymphomaNF-kB signalingBCR signal inhibitorsB cell precursorsCell of originCell viabilityChronic active BCRB cell survivalB cell receptor signalsHodgkin's diseaseMultiple myelomaNormal B cell developmentPlasma cellsBtk tyrosine kinaseCell lymphomaBurkitt's lymphomaNF-kBSmall molecule inhibitorsImmunoglobulin Light Chains Control Permissiveness to Malignant B-Cell Transformation By RAS-Pathway Lesions
Chan L, Kume K, Hurtz C, Robinson M, Cosgun K, Müschen M. Immunoglobulin Light Chains Control Permissiveness to Malignant B-Cell Transformation By RAS-Pathway Lesions. Blood 2023, 142: 2974. DOI: 10.1182/blood-2023-190163.Peer-Reviewed Original ResearchJeKo-1 cellsB cell precursorsMature B cellsB cellsMantle cell lymphoma cellsCell lymphoma cellsGenetic ablationImmunoglobulin light chainsRAS activationOncogenic RASMalignant transformationB-cell acute lymphoblastic leukemiaConventional light chainsRAS pathwayLymphoma cellsCell deathOncogenic RAS activationLight chainAcute lymphoblastic leukemiaMature B-cell lymphomasTransgenic mouse modelB-cell lymphomaB-cell malignanciesMalignant B-cell transformationKappa-LC
2021
Identification of BCL6 As Synthetic Lethality in RAS-Driven B-Cell Transformation
Chan L, Hurtz C, Leveille E, Kume K, Robinson M, Geng H, Cosgun K, Müschen M. Identification of BCL6 As Synthetic Lethality in RAS-Driven B-Cell Transformation. Blood 2021, 138: 792. DOI: 10.1182/blood-2021-148653.Peer-Reviewed Original ResearchRAS-ERK pathwayB cell developmentNormal B cell developmentRAS-ERKCell deathTransplant recipient miceSynthetic lethalityGenetic lesionsBCL6 expressionGenetic ablationChIP-seq analysisRAS-ERK signalingPermanent activationMurine B cell precursorsB cell precursorsDeletion of Bcl6Pharmacological inhibitionDoxycycline-inducible expressionSmall molecule inhibitionNegative B cell selectionSmall molecule inhibitorsExpression of PRDM1BCL6 promoterB-cell transformationExpression of BCL6
2019
Lgr5 Functions As a Critical Negative Regulator of Wnt/β-Catenin Signaling and Is Essential for B-Lymphopoiesis and Malignant B-Cell Transformation
Cosgun K, Deb G, Yang X, Xiao G, Sadras T, Lee J, Chan L, Kume K, Yang L, Geng H, Chan J, Song J, Jumaa H, Polson A, Clevers H, Müschen M. Lgr5 Functions As a Critical Negative Regulator of Wnt/β-Catenin Signaling and Is Essential for B-Lymphopoiesis and Malignant B-Cell Transformation. Blood 2019, 134: 748. DOI: 10.1182/blood-2019-127263.Peer-Reviewed Original ResearchB-cell lineage acute lymphoblastic leukemiaWnt/β-catenin signalingΒ-catenin signalingNuclear β-cateninAntibody-drug conjugatesB cell developmentB cell survivalΒ-cateninB lymphopoiesisFunction of LGR5Median mRNA levelsTime of diagnosisPoor clinical outcomeRole of LGR5Acute lymphoblastic leukemiaB-cell lymphomaLeukemia initiating cellsWnt/β-cateninHigh surface expressionMalignant B-cell transformationCell linesB cell precursorsTypes of cancerHuman colon cancer cell linesB-cell lineageIfitm3 Is Essential for PI(3,4,5)P3-Dependent B-Cell Activation and Leukemogenesis
Lee J, Xiao G, Cosgun K, Geng H, Ma N, Chan L, Kume K, Nix M, Chen Z, Chen C, Chen J, Khairnar V, Wiita A, Thomas-Tikhonenko A, Farzan M, Diamond M, Jung J, Vaidehi N, Müschen M. Ifitm3 Is Essential for PI(3,4,5)P3-Dependent B-Cell Activation and Leukemogenesis. Blood 2019, 134: 2782. DOI: 10.1182/blood-2019-127615.Peer-Reviewed Original ResearchPoor clinical outcomeB cellsBCR-ABL1Clinical outcomesPI3KAntigen-specific humoral immune responsesAntigen-specific B cell responsesAntiviral effector functionsTime of diagnosisMRNA levelsB cell responsesHumoral immune responseSurface expressionB cell populationsB-cell malignanciesB-cell receptor signalingDependent B cell activationTransplant recipient miceMalignant B-cell transformationB cell activationB cell precursorsColony formation capacityAdvisory CommitteeSrc kinaseB-cell transformation
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
2016
Oncogenic Feedback Activation Between BCL6 and MLL Promotes Malignant Transformation in MLL-RearrangedAcute Lymphoblastic Leukemia
Hurtz C, Chan L, Ballabio E, Willman C, Carroll W, Armstrong S, Ernst P, Melnick A, Milne T, Müschen M. Oncogenic Feedback Activation Between BCL6 and MLL Promotes Malignant Transformation in MLL-RearrangedAcute Lymphoblastic Leukemia. Blood 2016, 128: 907. DOI: 10.1182/blood.v128.22.907.907.Peer-Reviewed Original ResearchFunction of Bcl6Lymphoblastic leukemiaMLL-AF4Expression levelsPhiladelphia chromosome-positive acute lymphoblastic leukemiaBCL6 levelsPharmacological inhibitionDiffuse large B-cell lymphomaLarge B-cell lymphomaChemotherapy drugs vincristineTime of diagnosisWorse clinical outcomesBCL6 expressionHigh expression levelsRelapse-free survivalAcute lymphoblastic leukemiaChronic myeloid leukemiaB-cell lymphomaHigh-risk regimenMLL-ENLTransplant recipient miceB cell precursorsReporter mouse modelWestern blot analysisClinical outcomes
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 cellsSelf-Enforcing Feedback Activation Between BCL6 and Tonic Pre-B Cell Receptor Signaling in Acute Lymphoblastic Leukemia
Geng H, Hurtz C, Baumjohann D, Chen Z, Chen W, Ballabio E, Xiao G, Lee J, Deucher A, Qi Z, Huang C, Nahar R, Kweon S, Shojaee S, Chan L, Yu J, Tyner J, Chang B, Kornblau S, Bijl J, Ye B, Paietta E, Melnick A, Roeder R, Hunger S, Loh M, Milne T, Muschen M. Self-Enforcing Feedback Activation Between BCL6 and Tonic Pre-B Cell Receptor Signaling in Acute Lymphoblastic Leukemia. Blood 2014, 124: 284. DOI: 10.1182/blood.v124.21.284.284.Peer-Reviewed Original ResearchPre-BCR expressionB cell receptorInhibition of BCL6Patient-derived preTreatment of patientsMature B-cell lymphomasB-cell lymphomaPre-BCR signalingTCF3-PBX1Cell lymphomaMouse modelCell receptorDeletion of Bcl6Time of diagnosisBCL6 expressionPoor clinical outcomeAcute lymphoblastic leukemiaNovel mouse modelFeedback activationTranscription factor Bcl6Genetic mouse modelsB cell precursorsInhibition of SykHeavy chain expressionLineage-specific deletion
2013
Identification Of FOXM1 As Therapeutic Target In BCR-ABL1 Positive Acute Lymphoblastic Leukemia
Buchner M, Park E, Klemm L, Geng H, Kopanja D, Raychaudhuri P, Muschen M. Identification Of FOXM1 As Therapeutic Target In BCR-ABL1 Positive Acute Lymphoblastic Leukemia. Blood 2013, 122: 1250. DOI: 10.1182/blood.v122.21.1250.1250.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsAcute lymphoblastic leukemiaPositive acute lymphoblastic leukemiaPoor clinical outcomeFoxM1 expression levelBCR-ABL1Clinical outcomesB cell precursorsImatinib treatmentLymphoblastic leukemiaDisease progressionBreakpoint cluster regionTherapeutic targetBCR-ABL1 tyrosine kinase activityCatalase expressionPhiladelphia chromosome-positive acute lymphoblastic leukemiaSmall molecule tyrosine kinase inhibitorsFoxm1 deletionExpression levelsMolecule tyrosine kinase inhibitorsCell precursorsDeletion of Foxm1Münster Study GroupGood clinical responseIntracellular reactive oxygen species (ROS) formation
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 precursorsSOX4 enables Oncogenic Survival Signals in Acute Lymphoblastic Leukemia
Ramezani-Rad P, Geng H, Chan L, Hurtz C, Jumaa H, Melnick A, Paietta E, Carroll W, Willman C, Lefebvre V, Muschen M. SOX4 enables Oncogenic Survival Signals in Acute Lymphoblastic Leukemia. Blood 2012, 120: 863. DOI: 10.1182/blood.v120.21.863.863.Peer-Reviewed Original ResearchARF/p53PI3K/AktTranscription factorsPoor clinical outcomeNegative regulationBCR-ABL1B cell precursorsPre-B cell transitionClinical outcomesDe-phosphorylation eventsCpG methylation analysisMRNA levelsPre-B cell receptor checkpointMyeloid leukemiaP110 catalytic subunitCytokine receptor signalingB cell developmentB-cell lineage leukemiaSOX4 transcription factorTyrosine kinase inhibitor treatmentPI3K/Akt pathwayCell precursorsT cell developmentCritical upstream regulatorPutative DNAIdentification of FoxM1 As Therapeutic Target in TKI-Resistant Ph+ ALL
Buchner M, Klemm L, Zhengshan C, Geng H, Muschen M. Identification of FoxM1 As Therapeutic Target in TKI-Resistant Ph+ ALL. Blood 2012, 120: 874. DOI: 10.1182/blood.v120.21.874.874.Peer-Reviewed Original ResearchB cell precursorsLymphoblastic leukemiaTherapeutic targetPhiladelphia chromosome-positive acute lymphoblastic leukemiaPositive acute lymphoblastic leukemiaARF peptidesCell precursorsTreatment of TKIMajority of patientsTime of diagnosisAcute lymphoblastic leukemiaPatient-derived xenograftsValid therapeutic targetEffects of TKIsPotential therapeutic agentForkhead box transcription factor familyCell cycleSuperoxide dismutase expressionG0/G1Thiostrepton treatmentTKI treatmentPoor outcomeCombination therapyFl miceClinical trialsTargeting the UPR-Transcription Factor XBP1 to Overcome Drug-Resistance in Ph+ ALL
Masouleh B, Hurtz C, Geng H, Ramezani-Rad P, Glimcher L, Muschen M. Targeting the UPR-Transcription Factor XBP1 to Overcome Drug-Resistance in Ph+ ALL. Blood 2012, 120: 872. DOI: 10.1182/blood.v120.21.872.872.Peer-Reviewed Original ResearchX-box binding protein 1Relapse-free survivalMultiple myelomaSTF-083010Overall survivalPlasma cellsMinimal residual disease statusPKR-like ER kinaseOnset of chemotherapyLeukemia cellsResidual disease statusPoor overall survivalInducible CreImproved treatment optionsPlasma cell malignancyBone marrow B cell precursorsBone marrow progenitor cellsPresence of IL7ER stressTransplant recipient micePotential clinical relevanceUnfolded protein responseNormal bone marrowB cell precursorsMarrow progenitor cells
2011
Targeting Survivin with YM155 As a Potential Therapy in Pediatric Acute Lymphoblastic Leukemia
Jemal A, Tyner J, Thayer M, Muschen M, Druker B, Chang B. Targeting Survivin with YM155 As a Potential Therapy in Pediatric Acute Lymphoblastic Leukemia. Blood 2011, 118: 2490. DOI: 10.1182/blood.v118.21.2490.2490.Peer-Reviewed Original ResearchPediatric acute lymphoblastic leukemiaAcute lymphoblastic leukemiaLymphoblastic leukemiaPatient samplesPrimary patientsCell linesActivation of apoptosisPediatric B-cell precursorHematopoietic stem cell transplantSelective survivin suppressantStandard intensive chemotherapyEarly phase I studiesSubset of patientsStem cell transplantPhase I studiesCommon pediatric malignancyB-cell malignanciesPrimary patient samplesB cell precursorsLymphoblastic cell linesAdditional therapyIntensive chemotherapyCell transplantCombination therapyPediatric malignanciesPre-B Cell Receptor-Mediated Activation of BCL6 Induces Pre-B Cell Quiescence Through Transcriptional Repression of MYC
Nahar R, Ramezani-Rad P, Mossner M, Duy C, Cerchietti L, Geng H, Jumaa H, Ye B, Melnick A, Muschen M. Pre-B Cell Receptor-Mediated Activation of BCL6 Induces Pre-B Cell Quiescence Through Transcriptional Repression of MYC. Blood 2011, 118: 1406. DOI: 10.1182/blood.v118.21.1406.1406.Peer-Reviewed Original ResearchPre-B cell receptorCell receptorCell cycle exitExit cell cycleInitial proliferative burstAcute lymphoblastic leukemiaCycle exitB cell precursorsPre-B cell receptor signalingInducible activationTranscriptional repressor BCL6Receptor-Mediated ActivationCell receptor signalingInduction of quiescenceLymphoblastic leukemiaCell surface expressionOverexpression of MYCCCND2 expressionCell cycleBcl6-deficient miceMalignant transformationReceptor signalingReceptors resultsCell precursorsReceptors
2010
The Tumor Suppressor PTEN Is Required to Prevent Cellular Senescence and Cell Cycle Arrest In B Cell Lineage and Chronic Myeloid Leukemia
Shojaee S, Garcia C, Wu H, Muschen M. The Tumor Suppressor PTEN Is Required to Prevent Cellular Senescence and Cell Cycle Arrest In B Cell Lineage and Chronic Myeloid Leukemia. Blood 2010, 116: 513. DOI: 10.1182/blood.v116.21.513.513.Peer-Reviewed Original ResearchB-cell lineage leukemiaCML-like leukemiaChronic myeloid leukemiaB-cell lineageAcute lymphoblastic leukemiaDeletion of PTENLeukemia stem cellsCell cycle arrestT-cell lineageBCR-ABL1Myeloid leukemiaB cell precursorsCellular senescencePI3K/AktCell lineagesLeukemia cell growthEmpty vector controlLeukemia cellsTumor suppressorCML cellsSolid tumorsCycle arrestWestern blotCell precursorsStem cells
2009
BCL6-Dependent Negative Regulation of Cell Cycle Checkpoint Regulators Enables Drug-Resistance in Ph+ Acute Lymphoblastic Leukemia.
Duy C, Cerchietti L, Yu J, Ci W, Swaminathan S, Nahar R, Kweon S, Klemm L, Ye B, Melnick A, Müschen M. BCL6-Dependent Negative Regulation of Cell Cycle Checkpoint Regulators Enables Drug-Resistance in Ph+ Acute Lymphoblastic Leukemia. Blood 2009, 114: 765. DOI: 10.1182/blood.v114.22.765.765.Peer-Reviewed Original ResearchB-cell lymphomaTyrosine kinase inhibitorsCell lymphomaBCR-ABL1TKI treatmentCheckpoint regulatorsBCR-ABL1 tyrosine kinase inhibitorsCell cycle checkpoint regulatorsNOD/SCID miceFunction of Bcl6Leukemia cell injectionTreatment of patientsAcute lymphoblastic leukemiaCombination of imatinibCombination of nilotinibKinase inhibitor nilotinibB-cell lymphoma cellsPeptide inhibitionPotential therapeutic usefulnessFunction experimentsB cell precursorsCell lymphoma cellsTranscriptional suppressionQuantitative RT-PCRMedian survivalBCL6 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
2008
The Pre-B Cell Receptor Suppresses Leukemogenesis by Censoring MYC Expression.
Nahar R, Trageser D, Klemm L, Duy C, van Essen P, Kim Y, Heisterkamp N, Martinelli G, Hofmann W, Jack H, Jumaa H, Muschen M. The Pre-B Cell Receptor Suppresses Leukemogenesis by Censoring MYC Expression. Blood 2008, 112: 1918. DOI: 10.1182/blood.v112.11.1918.1918.Peer-Reviewed Original ResearchPre-B cell receptorPre-B cell receptor expressionPre-B cell receptor signalingFunctional pre-B cell receptorEarly pre-B cell stagePre-B cell stageCell receptor signalingSubstantial growth advantageB cell precursorsCell stageE2A-PBX1Receptor signalingCell receptorCell precursorsEarly B cell developmentGrowth advantageComparative gene expressionMYC expressionMLL-AF4Cell receptor expressionB cell developmentMYC mRNA levelsHeavy chain locusHigh expression levelsBCR-ABL1 oncogene