2015
Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia
Geng H, Hurtz C, Lenz KB, Chen Z, Baumjohann D, Thompson S, Goloviznina NA, Chen WY, Huan J, LaTocha D, Ballabio E, Xiao G, Lee JW, Deucher A, Qi Z, Park E, Huang C, Nahar R, Kweon SM, Shojaee S, Chan LN, Yu J, Kornblau SM, Bijl JJ, Ye BH, Ansel KM, Paietta E, Melnick A, Hunger SP, Kurre P, Tyner JW, Loh ML, Roeder RG, Druker BJ, Burger JA, Milne TA, Chang BH, Müschen M. Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia. Cancer Cell 2015, 27: 409-425. PMID: 25759025, PMCID: PMC4618684, DOI: 10.1016/j.ccell.2015.02.003.Peer-Reviewed Original ResearchMeSH KeywordsBasic Helix-Loop-Helix Transcription FactorsClinical Trials as TopicDNA-Binding ProteinsGene Expression Regulation, NeoplasticHumansIntracellular Signaling Peptides and ProteinsMolecular Sequence DataPhosphatidylinositol 3-KinasePre-B-Cell Leukemia Transcription Factor 1Precursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidProtein-Tyrosine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-6Signal TransductionSrc-Family KinasesSyk KinaseUp-RegulationConceptsDistinct subtypesPre-BCR signalingPatient-derived preVivo treatment studiesTreatment of patientsAcute lymphoblastic leukemiaTyrosine kinase inhibitorsPre-B cell receptor signalingCell receptor signalingLymphoblastic leukemiaClinical trialsTreatment studiesPre-BCR functionReceptor signalingKinase inhibitorsDistinct subsetsBCL6 expressionInduced activationFeedback activationSubtypesTyrosine kinaseBCL6SignalingActivationTranscriptional level
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
2011
BCL6-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 inhibitorsBCL6BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR–ABL1 kinase inhibition
Duy C, Hurtz C, Shojaee S, Cerchietti L, Geng H, Swaminathan S, Klemm L, Kweon SM, Nahar R, Braig M, Park E, Kim YM, Hofmann WK, Herzog S, Jumaa H, Koeffler HP, Yu JJ, Heisterkamp N, Graeber TG, Wu H, Ye BH, Melnick A, Müschen M. BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR–ABL1 kinase inhibition. Nature 2011, 473: 384-388. PMID: 21593872, PMCID: PMC3597744, DOI: 10.1038/nature09883.Peer-Reviewed Original ResearchMeSH KeywordsADP-Ribosylation Factor 1AnimalsCell SurvivalDNA-Binding ProteinsDrug Resistance, NeoplasmFusion Proteins, bcr-ablGene Expression Regulation, NeoplasticHumansMiceMice, Inbred NODMice, SCIDPrecursor Cell Lymphoblastic Leukemia-LymphomaProtein Kinase InhibitorsProto-Oncogene Proteins c-bcl-6Transcription, GeneticTumor Suppressor Protein p53ConceptsTyrosine kinase inhibitorsAcute lymphoblastic leukemia cellsBCR-ABL1 mutationsLymphoblastic leukemia cellsDrug resistanceLeukemia cellsLeukemia-initiating cellsXenograft modelBCR-ABL1Anticancer responseTargeted inhibitionDual inhibitionKinase inhibitorsOncogene withdrawalCancer therapyBCL6Kinase inhibitionLeukemiaInhibitionCellsTherapyMutationsUpregulation
2010
ROR1 as a Therapeutic Target In E2A-PBX1-Positive Acute Lymphoblastic Leukemia
Bicocca V, Chang B, Muschen M, Druker B, Tyner J. ROR1 as a Therapeutic Target In E2A-PBX1-Positive Acute Lymphoblastic Leukemia. Blood 2010, 116: 539. DOI: 10.1182/blood.v116.21.539.539.Peer-Reviewed Original ResearchReceptor tyrosine kinase-like orphan receptor 1Acute lymphoblastic leukemiaPositive cell linesLymphoblastic leukemiaMononuclear cellsLeukemia patientsE2A-PBX1Cytogenetic subtypesCell linesPatient samplesPositive acute lymphoblastic leukemiaKinase inhibitorsB-cell precursor phenotypeTyrosine kinaseCommon pediatric cancerKinase-like orphan receptor 1Novel therapeutic toolTyrosine kinase expressionKinase inhibitor dasatinibOrphan receptor 1Aberrant tyrosine kinase activityCell viabilityMTS cell viability assaysPrimary cellsPathogenesis of leukemiaABL 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