2019
Identification of ZNF217 As an Essential Oncogenic Gene in B-Cell Acute Lymphoblastic Leukemia By CRISPR/Cas9-Based Library Screening
Qin X, Su R, Yang L, Chan A, Deng X, Qing Y, Klemm L, Müschen M, Chen C, Chen J. Identification of ZNF217 As an Essential Oncogenic Gene in B-Cell Acute Lymphoblastic Leukemia By CRISPR/Cas9-Based Library Screening. Blood 2019, 134: 1465. DOI: 10.1182/blood-2019-129849.Peer-Reviewed Original ResearchB-cell acute lymphoblastic leukemiaBCR-ABL1 fusionAcute lymphoblastic leukemiaAcute myeloid leukemiaAML cellsM6A regulatorsMLL-AF4 fusionAdult patientsLymphoblastic leukemiaPediatric B-cell acute lymphoblastic leukemiaEssential oncogenic roleM6A modificationMessenger RNACytogenetic characteristicsDismal survivalMyeloid leukemiaB cell progenitorsTherapeutic targetOncogenic roleSolid tumorsPatientsZinc finger protein 217B-lineageLeukemiaCytogenetic changes
2016
Identification of the Energy Stress Sensor AMPK As Therapeutic Target in Acute Lymphoblastic Leukemia
Chan L, Lee J, Cosgun K, Geng H, Xiao G, Chen Z, Ernst T, Hochhaus A, Müschen M. Identification of the Energy Stress Sensor AMPK As Therapeutic Target in Acute Lymphoblastic Leukemia. Blood 2016, 128: 2771. DOI: 10.1182/blood.v128.22.2771.2771.Peer-Reviewed Original ResearchChronic myeloid leukemiaAcute lymphoblastic leukemiaMyeloid leukemiaTransplant recipient miceB-cell lineageLKB1/AMPKLymphoblastic leukemiaRecipient miceCML cellsTherapeutic targetLong-term disease-free survivalPhiladelphia chromosome-positive acute lymphoblastic leukemiaB-cell lineage leukemiaPatient-derived preDisease-free survivalInducible deletionNovel therapeutic targetGlycolytic activityBCR-ABL1 tyrosine kinaseNovel therapeutic avenuesATP levelsMitochondrial functionCell deathInitial remissionClinical characteristics
2015
Targeting 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 modalitiesB-Lymphoid Transcription Factors Restrict Glycolytic Energy Supply for Oncogenic Signaling
Chan L, Chen Z, Braas D, Geng H, Hurtz C, Shojaee S, Cazzaniga V, Ng C, Ernst T, Hochhaus A, Kornblau S, Cazzaniga G, Liu G, Milne T, Koeffler H, Armstrong S, Dickins R, Yamamoto K, Graeber T, Muschen M. B-Lymphoid Transcription Factors Restrict Glycolytic Energy Supply for Oncogenic Signaling. Blood 2015, 126: 1255. DOI: 10.1182/blood.v126.23.1255.1255.Peer-Reviewed Original ResearchGlycolytic energy supplyLKB1-AMPKB cellsTranscription factorsGlucose uptakeMyeloid leukemiaMyeloid malignanciesDeletion of Lkb1Unknown functional significanceB-lineage leukemiasTranscriptional repressionTranscriptional programsMyeloid leukemia cellsLineage conversionHematopoietic progenitor cellsOncogenic signalingClinical characteristicsLineage shiftGenetic lesionsCell deathGlycolytic reserveOncogenic lesionsLeukemia casesInsulin receptorGlucocorticoid receptor
2014
The 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 inhibitors
2013
Normal 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 mutationGas7 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
2012
SOX4 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 DNABCL6 Interacting Corepressor (BCOR) Functions As Lineage-Specific Tumor Suppressor in B Lymphoid and Myeloid Leukemia
Shojaee S, Geng H, Gearhart M, Bardwell V, Muschen M. BCL6 Interacting Corepressor (BCOR) Functions As Lineage-Specific Tumor Suppressor in B Lymphoid and Myeloid Leukemia. Blood 2012, 120: 1301. DOI: 10.1182/blood.v120.21.1301.1301.Peer-Reviewed Original ResearchB-cell lineageMyeloid leukemiaLeukemia cellsBCR-ABL1B-lymphoidTKI sensitivityBCOR overexpressionLoxP-flanked STOP cassetteCML-like leukemiaProgenitor cellsTumor suppressorBone marrow hematopoietic stemAcute myeloid leukemiaBone marrow progenitor cellsCell lineagesMarrow progenitor cellsTumor suppressor roleMyelodysplastic syndromeMale miceTKI resistanceCML cellsLoxP-flanked allelesFatal diseaseTumor growthLeukemia types
2011
BCL6-Mediated Repression of p53 Is Critical for Leukemia Stem Cell Survival in Chronic Myeloid Leukemia
Hurtz C, Hatzi K, Cerchietti L, Park E, Kim Y, Ramezani-Rad P, Jumaa H, Muller M, Hofmann W, Hochhaus A, Agarwal A, Shah N, Melnick A, Druker B, Muschen M. BCL6-Mediated Repression of p53 Is Critical for Leukemia Stem Cell Survival in Chronic Myeloid Leukemia. Blood 2011, 118: 446. DOI: 10.1182/blood.v118.21.446.446.Peer-Reviewed Original ResearchBCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia
Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM, Herzog S, Ramezani-Rad P, Jumaa H, Müller MC, Hofmann WK, Hochhaus A, Ye BH, Agarwal A, Druker BJ, Shah NP, Melnick AM, Müschen M. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. Journal Of Experimental Medicine 2011, 208: 2163-2174. PMID: 21911423, PMCID: PMC3201200, DOI: 10.1084/jem.20110304.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CD34BenzamidesCell SurvivalDisease Models, AnimalDNA-Binding ProteinsForkhead Transcription FactorsHematopoietic Stem CellsHumansImatinib MesylateLeukemia, Myelogenous, Chronic, BCR-ABL PositiveMiceMice, Inbred NODMice, KnockoutMice, SCIDNeoplasm TransplantationNeoplastic Stem CellsPiperazinesProtein Kinase InhibitorsProtein-Tyrosine KinasesProto-Oncogene Proteins c-bcl-6PyrimidinesTumor Cells, CulturedTumor Suppressor Protein p53ConceptsChronic myeloid leukemiaLeukemia-initiating cellsCML-initiating cellsTyrosine kinase inhibitorsTKI treatmentCML patientsMyeloid leukemiaCML cellsInhibition of BCL6Leukemia stem cell survivalLeukemia initiationHuman CML cellsColony formationBCR-ABL1 tyrosine kinaseInitiation of leukemiaTransplant recipientsBlast crisis transformationRepression of p53Pharmacological inhibitionStem cell survivalCML samplesLeukemiaClinical validationKinase inhibitorsBCL6
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 cellsThe 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 cellsABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1
Thai M, Ting P, McLaughlin J, Cheng D, Müschen M, Witte O, Colicelli J. ABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1. Leukemia 2010, 25: 290-300. PMID: 21102429, PMCID: PMC3049868, DOI: 10.1038/leu.2010.268.Peer-Reviewed Original ResearchConceptsBCR-ABL1Imatinib-resistant diseaseFirst-line therapyAcute lymphocytic leukemiaChronic myeloid leukemiaBCR-ABL1 kinase activityABL kinase inhibitor imatinibKinase inhibitor imatinibBCR-ABL1 activityBone marrow cellsAbl kinase inhibitorsDrug-resistant mutantsLeukemic casesMyeloid leukemiaLymphocytic leukemiaCell-autonomous mechanismsETV6-ABL1Inhibitor imatinibTyrosine kinase fusion proteinActive tyrosine kinaseMarrow cellsHematopoietic malignanciesKinase inhibitorsKinase fusion proteinGene translocation
2009
BCL6 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 upregulationThe B Cell Mutator AID Promotes B Lymphoid Blast Crisis and Drug-Resistance in Chronic Myeloid Leukemia.
Klemm L, Duy C, Iacobucci I, von Levetzow G, Feldhahn N, Kim Y, Hofmann W, Jumaa H, Groffen J, Heisterkamp N, Martinelli G, Lieber M, Casellas R, Müschen M. The B Cell Mutator AID Promotes B Lymphoid Blast Crisis and Drug-Resistance in Chronic Myeloid Leukemia. Blood 2009, 114: 3274. DOI: 10.1182/blood.v114.22.3274.3274.Peer-Reviewed Original ResearchBCR-ABL1 mutationsChronic myeloid leukemiaLymphoid blast crisisB-lymphoid blast crisisBCR-ABL1 kinase domainImatinib resistanceCML cellsBCR-ABL1Gene copy number alterationsDrug resistanceLeukemia cellsOverall survivalMyeloid leukemiaBlast crisisFive-year overall survivalCopy number alterationsNOD/SCID miceMedian overall survivalTreatment of patientsExpression of CD19Imatinib-resistant clonesMechanisms of progressionKinase inhibitor imatinibPresence of imatinibConcentrations of imatinibLeukemia Stem Cells
Müschen M. Leukemia Stem Cells. 2009, 281-294. DOI: 10.1007/978-90-481-3040-5_13.Peer-Reviewed Original ResearchLeukemia stem cell populationAcute myeloid leukemiaChronic myeloid leukemiaLeukemia stem cellsMyeloid leukemiaLeukemia subtypesCell populationsSelf-renewal capacityStem cellsAcute lymphoblastic leukemia subtypesStem cell populationSubtype of leukemiaRecent dataInitiation of leukemiaLeukemia cell populationsMalignant stem cellsLeukemiaHematopoietic stem cellsExtensive self-renewal capacitySubtypesMulti-lineage potentialCellular origin