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 miceIdentification of BCL6 As a Therapeutic Target in RAS-Driven Acute Lymphoblastic Leukemia
Li Q, Hurtz C, Shojaee S, Chen Z, Geng H, Xiao G, Loh M, Ye B, Melnick A, Muschen M. Identification of BCL6 As a Therapeutic Target in RAS-Driven Acute Lymphoblastic Leukemia. Blood 2015, 126: 556. DOI: 10.1182/blood.v126.23.556.556.Peer-Reviewed Original ResearchTime of relapseAcute lymphoblastic leukemiaLymphoblastic leukemiaTherapeutic targetNOD/SCID miceInhibition of BCL6Conventional cytotoxic therapyBCL6 functionComplementary mouse modelsTransplant recipient miceTranscriptional repressor BCL6P53-dependent senescenceMEK inhibitor PD325901Patient-derived cellsInitial remissionTransplant recipientsLeukemia relapseInitial diagnosisPathway lesionsCytotoxic therapyRecipient miceSCID miceSame patientFatal leukemiaMouse model
2012
Targeting BCL6-Mediated Drug-Resistance in High-Risk Childhood ALL
Hurtz C, Ramezani-Rad P, Geng H, Kharabi B, Carroll W, Willman C, Armstrong S, Melnick A, Muschen M. Targeting BCL6-Mediated Drug-Resistance in High-Risk Childhood ALL. Blood 2012, 120: 776. DOI: 10.1182/blood.v120.21.776.776.Peer-Reviewed Original ResearchDiffuse large B-cell lymphomaMLL-AF4High expression levelsBCL6 expressionExpression levelsB-cell lineage leukemiaHigh-risk childhood leukemiaMinimal residual disease statusNOD/SCID miceLarge B-cell lymphomaAberrant expressionFunction of Bcl6High-risk childhoodOnset of chemotherapyResidual disease statusTime of diagnosisPoor clinical outcomeProtein levelsBCR-ABL1 kinase activityB-cell lymphomaHigh-risk regimenBone marrow precursor cellsTransplant recipient miceGenetic mouse modelsB cell precursorsFunctional Modulation of VLA6 in BCR-ABL1+ Pre-B Acute Lymphoblastic Leukemia.
Gang E, Hsieh Y, Geng H, Pham J, Muschen M, de Arcangelis A, Willman C, Carroll W, Georges-Labouesse E, Bonig H, Kim Y. Functional Modulation of VLA6 in BCR-ABL1+ Pre-B Acute Lymphoblastic Leukemia. Blood 2012, 120: 2565. DOI: 10.1182/blood.v120.21.2565.2565.Peer-Reviewed Original ResearchMedian survival timeAcute lymphoblastic leukemiaBCR/ABL1Tyrosine kinase inhibitorsBCR-ABL1Leukemia progressionDrug resistanceBone marrow environmentLeukemia cellsLymphoblastic leukemiaPre-B Acute Lymphoblastic LeukemiaFlow cytometryNOD/SCID micePoor clinical outcomeCell adhesion-mediated drug resistanceChronic myeloid leukemiaMinimal residual diseaseChemotherapy drug resistanceAdhesion-mediated drug resistanceAddition of tamoxifenNormal B cellsModels of leukemiaVivo deletionConditional knockout modelNilotinib treatment
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 cellsAdjuvant CD49d Blockade Eradicates Chemoresistant ALL
Hsieh Y, Park E, Jiang E, Dauber K, Chudziak D, Schaefer P, Klemm L, Scharman C, Kang E, Koo H, Loh M, Hofmann W, Heisterkamp N, Muschen M, Shimada H, Bonig H, Kim Y. Adjuvant CD49d Blockade Eradicates Chemoresistant ALL. Blood 2010, 116: 869. DOI: 10.1182/blood.v116.21.869.869.Peer-Reviewed Original ResearchAcute lymphocytic leukemiaNOD/SCID miceBone marrow cellsSCID miceSurvival timeB-lineage acute lymphocytic leukemiaCounter-receptor VCAM-1Drug resistanceNOD/SCID xenograft modelLong-term side effectsMarrow cellsChemotherapy-resistant leukemiaDose-limiting toxicityLeukemia cellsSaline-treated groupCell adhesion-mediated drug resistanceMedian survival timeImmunocompetent mouse modelRelapse of leukemiaSCID xenograft modelAcute lymphoblastic leukemiaMurine leukemiaProlonged survival timeNew treatment modalitiesAdhesion-mediated drug resistance
2009
BCL6-Dependent Negative Regulation of Cell Cycle Checkpoint Regulators Enables Drug-Resistance in Ph+ Acute Lymphoblastic Leukemia.
Duy C, Cerchietti L, Yu J, Ci W, Swaminathan S, Nahar R, Kweon S, Klemm L, Ye B, Melnick A, Müschen M. BCL6-Dependent Negative Regulation of Cell Cycle Checkpoint Regulators Enables Drug-Resistance in Ph+ Acute Lymphoblastic Leukemia. Blood 2009, 114: 765. DOI: 10.1182/blood.v114.22.765.765.Peer-Reviewed Original ResearchB-cell lymphomaTyrosine kinase inhibitorsCell lymphomaBCR-ABL1TKI treatmentCheckpoint regulatorsBCR-ABL1 tyrosine kinase inhibitorsCell cycle checkpoint regulatorsNOD/SCID miceFunction of Bcl6Leukemia cell injectionTreatment of patientsAcute lymphoblastic leukemiaCombination of imatinibCombination of nilotinibKinase inhibitor nilotinibB-cell lymphoma cellsPeptide inhibitionPotential therapeutic usefulnessFunction experimentsB cell precursorsCell lymphoma cellsTranscriptional suppressionQuantitative RT-PCRMedian survivalThe 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 imatinib
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 bloodPreclinical Evaluation of Adjuvant Therapy with AMD3100 for Drug Resistant Philadelphia Chromosome Positive and Negative ALL
Jiang E, Yu M, Hsieh Y, DeLaTorre B, Kadavallore A, Scharman C, Park E, Yang A, Muschen M, Groffen J, Heisterkamp N, Kim Y. Preclinical Evaluation of Adjuvant Therapy with AMD3100 for Drug Resistant Philadelphia Chromosome Positive and Negative ALL. Blood 2008, 112: 2922. DOI: 10.1182/blood.v112.11.2922.2922.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaNOD/SCIDDrug-resistant leukemia cellsResistant leukemia cellsLeukemia cellsPreclinical evaluationPre-clinical xenograft modelNOD/SCID miceAcute lymphoblastic leukemia cellsCombination of AMD3100Different chemotherapeutic regimensNew treatment modalitiesLong-term survivalPrimary lymphoid organsLymphoblastic leukemia cellsTail vein injectionFurther preclinical evaluationCXCL12-CXCR4 interactionProgression of leukemiaB cell precursorsHigh death rateInteraction of CXCL12Clear beneficial effectPhiladelphia Chromosome PositiveBone marrow fibroblastsAberrant 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