2023
Cell circuits between leukemic cells and mesenchymal stem cells block lymphopoiesis by activating lymphotoxin beta receptor signaling
Feng X, Sun R, Lee M, Chen X, Guo S, Geng H, Müschen M, Choi J, Pereira J. Cell circuits between leukemic cells and mesenchymal stem cells block lymphopoiesis by activating lymphotoxin beta receptor signaling. ELife 2023, 12: e83533. PMID: 36912771, PMCID: PMC10042536, DOI: 10.7554/elife.83533.Peer-Reviewed Original ResearchConceptsMesenchymal stem cellsLymphotoxin beta receptorLeukemic cellsBeta receptorsLeukemic cell growthBone marrow microenvironmentStem cellsTransplant recipientsAML cellsMyeloblastic leukemiaMouse modelBone marrowLeukemia growthLymphotoxin α1β2Marrow microenvironmentPharmacological disruptionLymphopoiesisReceptorsHematopoietic outputMolecular mechanismsErythropoiesisDNA damage response pathwayCell growthCellsPhysiological mechanisms
2016
mTOR Kinase Inhibitors Enhance Efficacy of TKIs in Preclinical Models of Ph-like B-ALL
Gotesman M, Vo T, Mallya S, Zhang Q, Shi C, Müschen M, Weinstock D, Mullighan C, Tasian S, Konopleva M, Fruman D. mTOR Kinase Inhibitors Enhance Efficacy of TKIs in Preclinical Models of Ph-like B-ALL. Blood 2016, 128: 2763. DOI: 10.1182/blood.v128.22.2763.2763.Peer-Reviewed Original ResearchEvent-free survivalTOR-KIsPDX modelsBone marrowInhibitor monotherapyInhibitor therapyMurine bone marrowPatient-derived xenograft modelsTyrosine kinase inhibitor imatinibCompelling preclinical rationaleRearrangements of CRLF2Daily oral gavageEnd of treatmentKinase inhibitor therapyPrior preclinical studiesKinase inhibitor imatinibPI3K/mTORMouse bone marrow cellsBone marrow cellsNormal mouse bone marrow cellsReata PharmaceuticalsTKI dasatinibMost patientsLeukemia burdenPreclinical rationale
2015
Overcoming 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
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
Gas7 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
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
2008
Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1
Trageser D, Duy C, Klemm L, Gruber T, Nahar R, Park E, Kim Y, Groffen J, Heisterkamp N, Hofmann W, Martinelli G, Williams R, Jumaa H, Muschen M. Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1. Blood 2008, 112: 15. DOI: 10.1182/blood.v112.11.15.15.Peer-Reviewed Original ResearchFunctional pre-B cell receptorAcute lymphoblastic leukemiaBCR-ABL1Pre-B cell receptorCell receptorBone marrowPre-B cell receptor functionTransgenic miceLeukemic transformationLeukemic growthNOD/SCID miceWeight lossLeukemia cellsReceptor selectionTransgenic mouse modelSignificant weight lossPre-B cell receptor signalingBCR-ABL1 expressionSigns of diseaseSurvival signalsEarly B cell developmentLeukemic infiltrationSplenic enlargementCell receptor signalingPeripheral bloodAberrant Splicing of the SLP65 SH2 Domain Enables Pre-B Cell Transformation and Compromises the Leukemia-Suppressive Function of the Pre-B Cell Receptor
Duy C, Klemm L, Nahar R, van Essen P, Sprangers M, Kim Y, Park E, Martinelli G, Heisterkamp N, Hofmann W, Jumaa H, Muschen M. Aberrant Splicing of the SLP65 SH2 Domain Enables Pre-B Cell Transformation and Compromises the Leukemia-Suppressive Function of the Pre-B Cell Receptor. Blood 2008, 112: 294. DOI: 10.1182/blood.v112.11.294.294.Peer-Reviewed Original ResearchBCR-ABL1Pre-B cell receptorEarly pre-B cell stageCell receptorPre-B cell stageNOD/SCID miceLeukemia cellsPre-B cell receptor signalingSigns of diseaseSplice variantsEarly B cell developmentLeukemic infiltrationQuantitative RT-PCRCell receptor signalingCell receptor engagementSCID miceBone marrowB cell developmentMalignant transformationPre-B-cell transformationLeukemic growthCell transformationInduction of differentiationGermline mutationsMiceBCL6-Mediated Survival Signaling Promotes Drug-Resistance in BCRABL1- Driven Acute Lymphoblastic Leukemia
Duy C, Yu J, Cerchietti L, Klemm L, Nahar R, Kim Y, Heisterkamp N, Martinelli G, Hofmann W, Jumaa H, Melnick A, Ye B, Muschen M. BCL6-Mediated Survival Signaling Promotes Drug-Resistance in BCRABL1- Driven Acute Lymphoblastic Leukemia. Blood 2008, 112: 295. DOI: 10.1182/blood.v112.11.295.295.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaGerminal center B cellsImatinib treatmentBCR-ABL1Bone marrowB cellsLymphoblastic leukemiaHuman BCR-ABL1NOD/SCID miceFunction of Bcl6Inhibition of BCL6Low-dose imatinibBCL6 expressionLeukemia cellsP53 signalingProtein levelsCombination of imatinibGerminal center B cell survivalTail vein injectionNovel treatment conceptsTranscriptional repressor BCL6B cell survivalLow proliferation rateRecipient miceSCID mice
2007
Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1.
Trageser D, Klemm L, Herzog S, Kim Y, Duy C, Hofmann W, Groffen J, Heisterkamp N, Jumaa H, Muschen M. Pre-B Cell Receptor Signaling Prevents Leukemic Transformation by BCR-ABL1. Blood 2007, 110: 2795. DOI: 10.1182/blood.v110.11.2795.2795.Peer-Reviewed Original ResearchPre-B cell receptorFunctional pre-B cell receptorImmunoglobulin heavy chain locusAcute lymphoblastic leukemiaBCR-ABL1Cell receptorSurvival signalsPre-B cell receptor signalingReceptor selectionEarly B cell developmentBone marrowPre-B cell receptor functionTransgenic miceLeukemic transformationCell receptor signalingRapid cell deathB cell developmentHuman BCR-ABL1Potent tumor suppressorHeavy chain locusPre B cellsSingle-cell PCRTransgenic mouse modelCell receptor functionB cell precursorsThe Balance between Myc and Bcl6 Determines Self-Renewal or Differentiation of Pre-B Cells.
Duy C, de Alboran I, Jumaa H, Muschen M. The Balance between Myc and Bcl6 Determines Self-Renewal or Differentiation of Pre-B Cells. Blood 2007, 110: 797. DOI: 10.1182/blood.v110.11.797.797.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaBCR-ABL1B cellsDownregulation of MYCImmature B cellsEarly B cell developmentB cell differentiationLymphoblastic leukemiaExpression of MYCB cell developmentNovo expressionLarge B-cell lymphomaBCR-ABL1 inhibitorsB-cell lymphomaGerminal center B cellsB-cell malignanciesDe novo expressionCell lymphomaBone marrowPre-B cell culturesPre B cellsLeukemic transformationInduction of differentiationIL7Expression of BCL6