2019
Autonomous Ca2+ Oscillations Reflect Oncogenic Signaling in B-ALL Cells
Kume K, Chen L, Lee J, Müschen M. Autonomous Ca2+ Oscillations Reflect Oncogenic Signaling in B-ALL Cells. Blood 2019, 134: 1253. DOI: 10.1182/blood-2019-130708.Peer-Reviewed Original ResearchBCR-ABL1Stromal interaction molecule 1Activation of NFATc1B cell receptorOncogenic kinase activityAutonomous Ca2Oncogenic signalingB cellsOscillatory Ca2Deletion of Stim1Poor clinical outcomeBCR-ABL1 kinase activityRole of SOCENormal B cellsCre-mediated deletionStrong cytotoxic responseStore-operated Ca2B cell survivalOncogenic kinasesClinical outcomesHodgkin's lymphomaB-ALLPump inhibitorsMouse modelKinase activityIfitm3 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
2018
Pre-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 functionAutonomous Ca2+ Oscillations Reflect Oncogenic BCR-Signaling in Multiple B-Cell Malignancies and Are Essential for Survival and Proliferation
Kume K, Chen L, Lee J, Muschen M. Autonomous Ca2+ Oscillations Reflect Oncogenic BCR-Signaling in Multiple B-Cell Malignancies and Are Essential for Survival and Proliferation. Blood 2018, 132: 1373. DOI: 10.1182/blood-2018-99-117315.Peer-Reviewed Original ResearchAutonomous Ca2B-cell malignanciesBCR signalingProliferation signalsTime of diagnosisExpression levelsINCA-6B-ALLCell deathMantle cell lymphomaMedian expression levelBCR-ABL1Store-operated Ca2Cell lymphomaHigh expression levelsGenetic experimentsT-cell factorMyeloma cellsPatient-derived xenograft modelsMultiple B-cell malignanciesSurvival signalsFunctional BCRSTIM1/2Relapse-free survivalB-cell lymphoma cells
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-PCRGenetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL
Schjerven H, Ayongaba EF, Aghajanirefah A, McLaughlin J, Cheng D, Geng H, Boyd JR, Eggesbø LM, Lindeman I, Heath JL, Park E, Witte ON, Smale ST, Frietze S, Müschen M. Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL. Journal Of Experimental Medicine 2017, 214: 793-814. PMID: 28190001, PMCID: PMC5339667, DOI: 10.1084/jem.20160049.Peer-Reviewed Original ResearchConceptsTumor suppressor functionHuman BCR-ABL1Target genesSuppressor functionDevelopmental stage-specific expressionGenome-wide chromatinStage-specific expressionWild-type IkarosTumor suppressor geneChromatin compactionIkaros functionGene pathwaysMultiple genesExpression analysisGenetic analysisInducible expressionTumor suppressorGenetic depletionCell surface markers CD34Suppressor geneGenesIkarosBCR-ABL1Cell acute lymphoblastic leukemiaLeukemic growth
2016
Feedback Regulation of STAT5 Is Critical to Balance MYC and BCL6-Dependent Transcriptional Programs That Regulate Cell Size and Glucose Metabolism
Chen Z, Geng H, Klemm L, Chan L, Daniel B, Alexander W, Willman C, Müschen M. Feedback Regulation of STAT5 Is Critical to Balance MYC and BCL6-Dependent Transcriptional Programs That Regulate Cell Size and Glucose Metabolism. Blood 2016, 128: 4069. DOI: 10.1182/blood.v128.22.4069.4069.Peer-Reviewed Original ResearchBCR-ABL1Survival rateMedian expressionAdult B-lineageFree survival rateOverall survival rateWorse clinical outcomesGroup of patientsHigh expression levelsLeukemia cellsMRNA levelsNOD-SCID miceMYC expressionTyrosine kinase inhibitorsBCR-ABL1 tyrosine kinaseExpression levelsKinase inhibitory regionMedical Research CouncilAdvisory CommitteeInhibition of mTORGlucose consumptionCOG trialsLeukemia regressionTyrosine kinaseClinical outcomes
2015
Targeted Activation of B Cell Autoimmunity Checkpoints in Acute Lymphoblastic Leukemia
Chen Z, Geng H, Lowell C, Weiss A, Hunger S, Melnick A, Muschen M. Targeted Activation of B Cell Autoimmunity Checkpoints in Acute Lymphoblastic Leukemia. Blood 2015, 126: 3716. DOI: 10.1182/blood.v126.23.3716.3716.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsB cell receptorAcute lymphoblastic leukemiaPre-BCR signalingB cellsB cell selectionLymphoblastic leukemiaBCR-ABL1Autoreactive B cell receptorsCell deathPre-B-cell originAcute lymphoblastic leukemia cellsCurrent therapy approachesLeukemia cellsWorse clinical outcomesSelf-reactive B cellsNegative B cell selectionPotent tyrosine kinase inhibitorLymphoblastic leukemia cellsNovel small molecule inhibitorTypes of cancerUbiquitous self-antigenClinical outcomesIncremental increasePoor outcomeTargeting of Quiescent and Proliferating CML Stem Cells By DNA Repair Inhibitors
Sullivan K, Bolton-Gillespie E, Nieborowska-Skorska M, Cerny-Reiterer S, Valent P, Muschen M, Pomerantz R, Mazin A, Skorski T. Targeting of Quiescent and Proliferating CML Stem Cells By DNA Repair Inhibitors. Blood 2015, 126: 50. DOI: 10.1182/blood.v126.23.50.50.Peer-Reviewed Original ResearchQuiescent leukemia stem cellsLeukemia stem cellsTyrosine kinase inhibitorsChronic myeloid leukemiaCML cellsBCR-ABL1Myeloid leukemiaAnti-leukemia effectSimultaneous targetingCML leukemia stem cellsNew treatment modalitiesPARP1 inhibitorsCML stem cellsNormal counterpartsDouble knockout miceAdditional chromosomal aberrationsTKI-resistant BCRStem cellsBristol-Myers SquibbTKI therapyDisease relapseChronic phaseGood respondersCML patientsTreatment modalitiesOvercoming Drug Resistance of Pre-B ALL Cells By Targeting Integrin alpha6 Associated Cell-Adhesion Mediated Drug Resistance Using a Novel Antibody, P5G10
Gang E, Hsieh Y, Kim H, Duchartre Y, Stephanie S, Muschen M, Wayner E, Heisterkamp N, Bonig H, Kim Y. Overcoming Drug Resistance of Pre-B ALL Cells By Targeting Integrin alpha6 Associated Cell-Adhesion Mediated Drug Resistance Using a Novel Antibody, P5G10. Blood 2015, 126: 2525. DOI: 10.1182/blood.v126.23.2525.2525.Peer-Reviewed Original ResearchMinimal residual diseaseTyrosine kinase inhibitorsPeripheral bloodDrug resistanceFlow cytometryLeukemia cellsRecipient miceHuman CD45Bone marrowBCR-ABL1NOD/SCID miceControl recipient miceCell adhesion-mediated drug resistanceAdhesion-mediated drug resistanceNovel therapeutic targetControl-treated cellsCell-bearing miceChemotherapy-resistant cellsPercentage of adherenceLaminin-1Integrin alpha 6Mesenchymal stromal cellsNormal hematopoietic cellsOvercoming Drug ResistanceUntreated mice
2014
Gene Expression and Mutation Analysis (GEMA) –Guided Precision Medicine Targeting PARP1 to Induce Synthetic Lethality in DNA-PK –Deficient Quiescent and BRCA-Deficient Proliferating Leukemia Stem and Progenitor Cells
Nieborowska-Skorska M, Sullivan K, Podszywalow-Bartnicka P, Hoser G, Bolton-Gillespie E, Cramer-Morales K, Slupianek A, Zhou C, Cerny-Reiterer S, Stoklosa T, Sykes S, Valent P, Civin C, Muschen M, Minden M, Eppert K, Skorski T. Gene Expression and Mutation Analysis (GEMA) –Guided Precision Medicine Targeting PARP1 to Induce Synthetic Lethality in DNA-PK –Deficient Quiescent and BRCA-Deficient Proliferating Leukemia Stem and Progenitor Cells. Blood 2014, 124: 480. DOI: 10.1182/blood.v124.21.480.480.Peer-Reviewed Original ResearchQuiescent leukemia stem cellsLeukemia progenitor cellsLeukemia stem cellsIndividual patientsPARP1 inhibitorsBCR-ABL1MLL-AF9Progenitor cellsHomologous recombination repairSurvival of miceAML1-ETOAnti-tumor treatmentBone marrow cellsQuiescent cellsMutation analysisCML-CPDisease burdenImmunodeficient miceTumor initiatingLeukemia xenograftsReduced colony formationPatientsPharmacological inhibitionDNA double-strand breaksRepair mechanismsBACH2 promotes Lineage-Specific Fate Decisions in BCR-ABL1-Driven Leukemia
Park E, Swaminathan S, Sadiyah M, Igarashi K, Melnick A, Muschen M. BACH2 promotes Lineage-Specific Fate Decisions in BCR-ABL1-Driven Leukemia. Blood 2014, 124: 513. DOI: 10.1182/blood.v124.21.513.513.Peer-Reviewed Original ResearchLymphoid blast crisisFate decisionsB-cell lineageCML-like diseaseCell lineagesTumor suppressorCML cellsBCR-ABL1Transcription factorsTransplant recipientsLineage-specific transcription factorsChronic phaseB-cell-specific transcription factorCell-specific transcription factorsBlast crisisPre-B cell receptor checkpointB-cell lineage leukemiaPrimary human CML cellsRole of Bach2Multi-lineage progenitor cellsEmpty vector controlGene expression analysisSelective proliferative advantagePotent tumor suppressorCML chronic phaseFOXM1 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 cellsThe Linker Protein GAS7 Negatively Regulates Pre-B Cell Differentiation and Amplifies Proliferation and Survival Signals in Acute Lymphoblastic Leukemia
Lee J, Buchner M, Geng H, Swaminathan S, Park E, Park A, Lin-Chao S, So C, Muschen M. The Linker Protein GAS7 Negatively Regulates Pre-B Cell Differentiation and Amplifies Proliferation and Survival Signals in Acute Lymphoblastic Leukemia. Blood 2014, 124: 3777. DOI: 10.1182/blood.v124.21.3777.3777.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaTyrosine kinase inhibitorsLymphoblastic leukemiaBCR-ABL1B-cell lineage leukemiaPre-B cell differentiationTyrosine kinase inhibitor treatmentPediatric acute lymphoblastic leukemiaTreatment-related acute myeloid leukemiaAcute myeloid leukemiaPre-B cell receptor checkpointKinase inhibitor treatmentEffects of Stat5Spontaneous IgNormal B cell developmentMyeloid leukemiaB cell progenitorsBone marrowCell differentiationInhibitor treatmentB cell developmentLeukemiaSelf-renewal capacityConditional deletionKinase inhibitorsPTEN Is Essential for Normal Cytokine Signaling and Oncogenic Transformation of Pre-B Cells
Shojaee S, Cazzaniga V, Schjerven H, Buchner M, Hurtz C, Geng H, Hochhaus A, Cazzaniga G, Melnick A, Kornblau S, Graeber T, Muschen M. PTEN Is Essential for Normal Cytokine Signaling and Oncogenic Transformation of Pre-B Cells. Blood 2014, 124: 262. DOI: 10.1182/blood.v124.21.262.262.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaAlleles of PTENDeletion of PTENPI3K-Akt pathwayPI3K-Akt signalingGlucocorticoid resistanceHuman preSmall molecule inhibitorsBCR-ABL1Expression levelsMyeloid lineage leukemiasPatient-derived prePTEN deletionT-cell acute lymphoblastic leukemiaCell acute lymphoblastic leukemiaHigh expression levelsLeukemia cellsTime of diagnosisPoor clinical outcomeCell deathMature B-cell lymphomasPTEN inhibitionHuman cancersLeukemia/lymphomaB-cell lymphoma
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) formationNormal ABL1 Is a Tumor Suppressor and Therapeutic Target In BCR-ABL1–positive Leukemias
Dasgupta Y, Koptyra M, Nieborowska-Skorska M, Gillespie E, Stoklosa T, Hoser G, Wasik M, Muschen M, Richardson C, Skorski T. Normal ABL1 Is a Tumor Suppressor and Therapeutic Target In BCR-ABL1–positive Leukemias. Blood 2013, 122: 1466. DOI: 10.1182/blood.v122.21.1466.1466.Peer-Reviewed Original ResearchLeukemia stem cellsCML-CPBCR-ABL1Myeloid differentiationCML blast phaseTumor suppressorEffect of imatinibChronic myeloid leukemiaNovel therapeutic strategiesABL1 kinaseHigher clonogenic activityPositive CML cellsStem cellsBCR-ABL1 kinaseImatinib-treated cellsPotential tumor suppressorChronic phaseCML treatmentLSC compartmentMyeloid leukemiaSCID miceCML CD34Blastic transformationOxidative DNA damageT315I mutationOncogene-Induced DNA Repair Defects Promote PARP1-Mediated “Dual Synthetic Lethality” To Eradicate Quiescent and Proliferating Leukemia Stem and Progenitor Cells
Nieborowska-Skorska M, Slupianek A, Hoser G, Bolton-Gillespie E, Tulin A, Cerny-Reiterer S, Valent P, Muschen M, Sykes S, Skorski T. Oncogene-Induced DNA Repair Defects Promote PARP1-Mediated “Dual Synthetic Lethality” To Eradicate Quiescent and Proliferating Leukemia Stem and Progenitor Cells. Blood 2013, 122: 810. DOI: 10.1182/blood.v122.21.810.810.Peer-Reviewed Original ResearchQuiescent leukemia stem cellsLeukemia progenitor cellsLeukemia stem cellsImatinib-naïveLeukemia cellsAML1-ETOBCR-ABL1PARP1 inhibitorsProgenitor cellsNormal cellsAnti-leukemia effectPositive AML cellsBCR-ABL1 T315I mutationInhibited colony formationAnti-proliferative effectsPARP inhibitor olaparibStem cellsModest inhibitory effectInhibition of PARPPeripheral bloodDisease burdenBone marrow nicheClinical trialsAML cellsT315I mutationIfitm3 (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 p53Gas7 Induces The Proliferation Of Ph+ ALL Cells and Prevents The Differentiation Of Early B Cell Progenitors Into CD25high Small Pre-B Cells
Lee J, Buchner M, Geng H, Swaminathan S, Park E, Klemm L, Lin-Chao S, So C, Muschen M. Gas7 Induces The Proliferation Of Ph+ ALL Cells and Prevents The Differentiation Of Early B Cell Progenitors Into CD25high Small Pre-B Cells. Blood 2013, 122: 2506. DOI: 10.1182/blood.v122.21.2506.2506.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaAcute myeloid leukemiaTyrosine kinase inhibitorsB cell progenitorsBCR-ABL1B cell developmentEarly B cell developmentCell progenitorsB-cell lineage leukemiaPediatric acute lymphoblastic leukemiaMotor neuron numberBone marrow B-cell progenitorsEffects of Stat5Growth arrest-specific gene 7Levels of p21Leukemia cell survivalExpression of intracellularLymphoblastic leukemiaIL7R expressionMyeloid leukemiaBone marrowB cellsInterleukin-7Pre B cellsSelf-renewal capacity