2023
Computational Discovery and Validation of NAD+ Biosynthesis As Unique Vulnerability in B-Lymphoid Malignancies
Li Q, Robinson M, Leveille E, Zhang C, Sun R, Cheng Z, Kume K, Cosgun K, Kothari S, Khanduja D, Nakada D, Müschen M. Computational Discovery and Validation of NAD+ Biosynthesis As Unique Vulnerability in B-Lymphoid Malignancies. Blood 2023, 142: 418. DOI: 10.1182/blood-2023-190269.Peer-Reviewed Original ResearchSmall molecule inhibitorsDrug discovery toolNAMPT inhibitorsCompound screenCell type-specific targetsCell linesMolecule inhibitorsPurine/pyrimidine metabolismTumor cell linesEnergy metabolismSalvage biosynthesis pathwaySolid tumor cell linesB cell developmentCellular energy metabolismB cell signalingAmino acid metabolismCell cycle arrestDiscovery toolDepletion of metabolitesBiosynthesis pathwayCompetitive fitnessRate-limiting enzymeNAMPT deletionConditional mouse modelEnergy stressMYC to BCL6 State-Transitions Determine Cell Size and Metabolic Fluctuations and Define a Novel Biorhythm in B-Cell Malignancies
Cheng Z, Kume K, Müschen M. MYC to BCL6 State-Transitions Determine Cell Size and Metabolic Fluctuations and Define a Novel Biorhythm in B-Cell Malignancies. Blood 2023, 142: 2769. DOI: 10.1182/blood-2023-190972.Peer-Reviewed Original ResearchGerminal center-derived B-cell lymphomaB cell developmentCell size fluctuationsCell cycleImmunoglobulin light chain gene recombinationDNA damage-induced apoptosisDistinct cellular statesNormal B cell developmentDamage-induced apoptosisExit cell cycleCell sizeB cell transitionGene expression profilesQuiescent phenotypeOncogenic tyrosine kinasesCell cycle arrestActivation of autophagySingle-cell sortingCellular statesCell divisionHigher glycolysis activityMYC transcriptionB cell cycleSuppression of glycolysisExpression profiles
2021
Beta-Catenin Forms Repressive Complexes with Ikzf1 and Ikzf3 to Orchestrate Tumor-Suppression in B-Cell Malignancies
Cosgun K, Robinson M, Chan L, Hur M, Leveille E, Song J, Chan W, Müschen M. Beta-Catenin Forms Repressive Complexes with Ikzf1 and Ikzf3 to Orchestrate Tumor-Suppression in B-Cell Malignancies. Blood 2021, 138: 29. DOI: 10.1182/blood-2021-148597.Peer-Reviewed Original ResearchB-cell malignanciesΒ-catenin activationΒ-cateninOncogenic Wnt/β-catenin signalingMalignant B-lymphoid cellsGenetic deletionRefractory B-ALLTranscriptional repressionB-cell lymphomaTumor suppressionWnt/β-catenin signalingΒ-catenin/TCF complexMature B-cell malignanciesB-lymphoid cellsCancer cell linesΒ-catenin signalingClonal fitnessOverall survivalLeukemia burdenNSG miceB-ALLCell cycle arrestNuclear β-cateninPan-cancer analysisFrequent lesions
2018
Ras-Driven B-Cell Transformation Targets Developmental Rewiring of Cytokine to Pre-B Cell Receptor Signaling
Chan L, Hurtz C, Geng H, Auer F, Chen Z, Xiao G, Lee J, Cosgun K, Ye B, Muschen M. Ras-Driven B-Cell Transformation Targets Developmental Rewiring of Cytokine to Pre-B Cell Receptor Signaling. Blood 2018, 132: 1336. DOI: 10.1182/blood-2018-99-115514.Peer-Reviewed Original ResearchPre-BCR signalingOncogenic Ras signalingOncogene-induced senescencePotential therapeutic intervention pointsCompetitive growth assaysInducible activationTherapeutic intervention pointCytokine receptorsRas signalingOncogenic RasPre-B cell receptor signalingCell transitionGenetic studiesPre-B cell receptorPre-B cell transitionIrreversible cell cycle arrestEarly B cell developmentLight chain gene expressionCell receptor signalingB cell developmentARF/p53Number of coloniesChain gene expressionDepletion of cellsCell cycle arrestPre-BCR Surrogate Light Chain Components VPREB1 and IGLL1 Function As Pre-BCR-Independent Tumor Suppressors in Acute Lymphoblastic Leukemia
Cosgun K, Hendriks R, Dickins R, Heisterkamp N, Muschen M. Pre-BCR Surrogate Light Chain Components VPREB1 and IGLL1 Function As Pre-BCR-Independent Tumor Suppressors in Acute Lymphoblastic Leukemia. Blood 2018, 132: 570. DOI: 10.1182/blood-2018-99-115522.Peer-Reviewed Original ResearchBCR-ABL1Transgenic miceSurrogate light chainTime of diagnosisTime of relapseDouble transgenic miceExerts tumor-suppressive effectsAcute lymphoblastic leukemiaB cell defectsDay of birthBCR-ABL1 tyrosine kinaseHigh surface levelsTumor-suppressive effectsPre-BCR expressionColony formation abilityPhosphorylation of BtkTumor suppressorBCR-ABL1 oncogeneEarly B cell developmentTumor suppressive functionLymphoblastic leukemiaCell cycle arrestFrequent lesionsSecondary lesionsSuppressive functionIFITM3-Mediated Regulation of Cell Membrane Dynamics Is Essential for Malignant B-Cell Transformation
Lee J, Geng H, Dinson D, Xiao G, Cosgun K, Chan L, Chen Z, Farzan M, Jung J, Wiita A, Muschen M. IFITM3-Mediated Regulation of Cell Membrane Dynamics Is Essential for Malignant B-Cell Transformation. Blood 2018, 132: 552. DOI: 10.1182/blood-2018-99-117472.Peer-Reviewed Original ResearchB cell receptorLipid raftsOncogenic tyrosine kinasesTyrosine kinasePlasma membraneCentral regulatorNormal B-cell receptorType II transmembrane topologyPI3KMalignant B-cell transformationIntracellular N terminusHomotypic cellular aggregationCell membraneCo-receptor CD19Assembly of membraneMRNA levelsLipid raft formationCell membrane dynamicsPotent tumor suppressorDifferent cell typesCholesterol accumulationCell cycle arrestCell receptorEndocytic motifTransmembrane topology
2015
IFITM3 (CD225) Links the B Cell Antigen CD19 to PI3K-AKT Signaling in Human ALL Cells
Lee J, Geng H, Chen Z, Eugene P, Klemm L, Bailey C, Muschen M. IFITM3 (CD225) Links the B Cell Antigen CD19 to PI3K-AKT Signaling in Human ALL Cells. Blood 2015, 126: 1325. DOI: 10.1182/blood.v126.23.1325.1325.Peer-Reviewed Original ResearchTime of diagnosisPI3K-Akt signalingPI3K-AktHuman preSurface expressionAgonistic antibodiesB-cell antigen CD19Patient-derived preRelapse-free survivalMRNA levelsChimeric antigen receptorMedian expression levelPI3K p110δSurface receptorsColony formation capacityMRD statusInduction chemotherapyImmunotherapy approachesAntigen CD19Cell cycle arrestCell receptor complexClinical trialsCD19 expressionHigh riskB cell progenitors
2014
IFITM3 (CD225) Regulates CD19 Surface Expression and CD19-Mediated Activation of PI3K Signaling in Pre-B Acute Lymphoblastic Leukemia Cells
Lee J, Geng H, Chen Z, Park E, Park A, Klemm L, Bailey C, Muschen M. IFITM3 (CD225) Regulates CD19 Surface Expression and CD19-Mediated Activation of PI3K Signaling in Pre-B Acute Lymphoblastic Leukemia Cells. Blood 2014, 124: 1070. DOI: 10.1182/blood.v124.21.1070.1070.Peer-Reviewed Original ResearchCD19-specific chimeric antigen receptorTime of diagnosisB cell progenitorsPI3K-AktSurface expressionCell cycle arrestC-myc expressionCD19 expressionCell progenitorsB cellsHuman preAcute lymphoblastic leukemia cellsLow-dose AdriamycinPatient-derived preSignificant inhibitionRelapse-free survivalG0/G1 cell cycle arrestMRNA levelsChimeric antigen receptorExpression of CD19Cycle arrestBCR-ABL1 activityG1 cell cycle arrestLymphoblastic leukemia cellsG0/G1 phase
2013
Ifitm3 (CD225) Mediates CD19-Dependent Survival and Proliferation During Normal B Cell Development and In Ph+ ALL
Lee J, Geng H, Chen Z, Park E, Klemm L, Bailey C, Muschen M. Ifitm3 (CD225) Mediates CD19-Dependent Survival and Proliferation During Normal B Cell Development and In Ph+ ALL. Blood 2013, 122: 2505. DOI: 10.1182/blood.v122.21.2505.2505.Peer-Reviewed Original ResearchB cell progenitorsC-myc expressionOverall survivalCell cycle arrestCell progenitorsB cellsBCR-ABL1Minimal residual disease statusResidual disease statusSignificant inhibitionTime of diagnosisG0/G1 cell cycle arrestHigh expression levelsPoor overall survivalExpression of CD19Treatment of adriamycinSurface expressionCycle arrestBCR-ABL1 activityG1 cell cycle arrestExpression levelsG0/G1 phaseCellular senescenceLow surface expressionLevels of p53Targeting Pre-B Cell Receptor and BCL6 In TCF3-PBX1 B-Lineage Acute Lymphoblastic Leukemia
Geng H, Hurtz C, Chen Z, Chen W, Ballabio E, Xiao G, Kweon S, Nahar R, Sojaee S, Chan L, Masouleh B, Sykes D, Melnick A, Roeder R, Milne T, Muschen M. Targeting Pre-B Cell Receptor and BCL6 In TCF3-PBX1 B-Lineage Acute Lymphoblastic Leukemia. Blood 2013, 122: 349. DOI: 10.1182/blood.v122.21.349.349.Peer-Reviewed Original ResearchPre-BCR signalingGene expression microarray dataB-lineage acute lymphoblastic leukemiaExpression microarray dataTyrosine kinase inhibitorsPre-B cell receptorCell deathMicroarray dataPre-BCR componentsPoor clinical outcomeAcute lymphoblastic leukemiaTCF3-PBX1Cell line 697Cell cycle arrestTranscriptional repressor BCL6ChIPseq dataPre-BCRChIP-seqCellular processesClinical outcomesCritical survival factorTherapeutic targetLeukemia cellsLymphoblastic leukemiaTransplant recipient mice
2010
IKAROS and BCL6 Limit Pre-B Cell Expansion and Prevent Leukemogenesis Downstream of the Pre-B Cell Receptor
Nahar R, Ramezani-Rad P, Duy C, Dovat S, Ye B, Melnick A, Muschen M. IKAROS and BCL6 Limit Pre-B Cell Expansion and Prevent Leukemogenesis Downstream of the Pre-B Cell Receptor. Blood 2010, 116: 146. DOI: 10.1182/blood.v116.21.146.146.Peer-Reviewed Original ResearchPre-B cell receptorCell cycle arrestCell cycle progressionTumor suppressorCycle arrestTumor suppressionIkaros functionCycle progressionNegative cell cycle regulationSignaling leadsDephosphorylation of STAT5Cell receptorIkaros expressionBCL6 transcriptional repressorGenome-wide ChIPPre-B cell expansionCell cycle regulationSubsequent cell cycle arrestCentral mediatorOverexpression of MYCProliferation downstreamTranscriptional repressionGenetic experimentsTranscriptional repressorTranscriptional activationMechanisms of Pre-B Cell Receptor-Inactivation In Acute Lymphoblastic Leukemia
Duy C, Nowak D, Klemm L, Nahar R, Ng C, Elliott E, Hofmann W, Heisterkamp N, Lowell C, Koeffler P, Muschen M. Mechanisms of Pre-B Cell Receptor-Inactivation In Acute Lymphoblastic Leukemia. Blood 2010, 116: 147. DOI: 10.1182/blood.v116.21.147.147.Peer-Reviewed Original ResearchPre-B cell receptorImmunoglobulin μ chainCell receptor functionCell receptor stimulationTyrosine kinasePAX5 fusion genesSystematic gene expression analysisΜ chainsSplice variantsCell receptorRapid cell cycle arrestExon 16Immunoglobulin gene rearrangementsReceptor functionReceptor signal transductionPre-B cell receptor functionGene rearrangementsGene expression analysisLeukemia cellsDominant-negative waySyk tyrosine kinaseCell cycle arrestPre B cellsSH2 domainMRNA splicingSYK Is a Tumor Suppressor In Pre-B Cell Acute Lymphoblastic Leukemia and Not a Therapeutic Target
Ng C, Nahar R, Elliott E, Lowell C, Muschen M. SYK Is a Tumor Suppressor In Pre-B Cell Acute Lymphoblastic Leukemia and Not a Therapeutic Target. Blood 2010, 116: 4199. DOI: 10.1182/blood.v116.21.4199.4199.Peer-Reviewed Original ResearchDeletion of SykPre-B leukemia cellsAcute lymphoblastic leukemiaPre-B cell receptor functionB-cell lymphomaImatinib treatmentTumor-suppressive effectsRole of SykPre-B cell receptorCell cycle arrestBCR-ABL1Cell receptorCritical survival signalsLeukemia cellsCell receptor signalingLymphoblastic leukemiaCell lymphomaSuppressive effectCycle arrestSyk tyrosine kinaseReceptor functionPre-B-cell acute lymphoblastic leukemiaWestern blotReceptor signalingPre-B cell receptor expressionThe 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
Inducible Ablation of HSPA5 Suppresses BCR-ABL1-Driven Leukemia through Massive Accumulation of Reactive Oxygen Species.
Chang M, Wey S, Lee A, Müschen M. Inducible Ablation of HSPA5 Suppresses BCR-ABL1-Driven Leukemia through Massive Accumulation of Reactive Oxygen Species. Blood 2009, 114: 1976. DOI: 10.1182/blood.v114.22.1976.1976.Peer-Reviewed Original ResearchCML-like leukemiaBCR-ABL1Bone marrowLeukemia cellsReactive oxygen speciesImatinib sensitivityNOD/SCID recipientsG0/G1 cell cycle arrestNovel therapeutic approachesP210 BCR-ABL1G1 cell cycle arrestBone marrow cellsLevels of ROSBone marrow microenvironmentCell deathLeukemia cell survivalSCID recipientsCytokine primingFl miceCell cycle arrestOxygen speciesTherapeutic approachesCML cellsDay 4Leukemia growthBCL6 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