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 rationaleBCOR regulates myeloid cell proliferation and differentiation
Cao Q, Gearhart M, Gery S, Shojaee S, Yang H, Sun H, Lin D, Bai J, Mead M, Zhao Z, Chen Q, Chien W, Alkan S, Alpermann T, Haferlach T, Müschen M, Bardwell V, Koeffler H. BCOR regulates myeloid cell proliferation and differentiation. Leukemia 2016, 30: 1155-1165. PMID: 26847029, PMCID: PMC5131645, DOI: 10.1038/leu.2016.2.Peer-Reviewed Original ResearchConceptsMyeloid cell proliferationHox genesCell proliferationFunction mutationsUbiquitin ligase subunitRNA expression profilingPolycomb groupEnhanced cell proliferationOverexpression allelesHOXA genesExpression profilingGene expressionConditional lossMyeloid differentiationMurine cellsFamily complexesNormal hematopoiesisGenesBone marrow cellsBCOR expressionProtein levelsMechanistic explanationDifferentiation rateAML patient samplesMutations
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 mechanisms
2010
ABL 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 translocationTargeting Survivin In Recalcitrant Acute Lymphoblastic Leukemia
Park E, Jiang E, Hsieh Y, Klemm L, Duy C, Conway E, Pelus L, Crispino J, Loh M, Kang E, Koo H, Yang A, Heisterkamp N, Kahn M, Muschen M, Kim Y. Targeting Survivin In Recalcitrant Acute Lymphoblastic Leukemia. Blood 2010, 116: 3263. DOI: 10.1182/blood.v116.21.3263.3263.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaMedian survival timeLymphoblastic leukemiaLong-term side effectsNucleic acid antisense oligonucleotideRelapse of leukemiaSurvivin shRNASingle-agent treatmentNew treatment modalitiesNOD/SCIDEvaluation of survivinInhibition of survivinCFU assayBone marrow cellsGFP controlFunction studiesKnockout mouse modelOverexpression of survivinAmgen IncLNA treatmentLeukemia relapseKnockdown of survivinTreatment modalitiesCurrent treatmentMouse modelAdjuvant 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
Activation-Induced Cytidine Deaminase Accelerates Clonal Evolution of BCR-ABL1-Driven B Cell Lineage Acute Lymphoblastic Leukemia.
Gruber T, Chang M, Sposto R, Müschen M. Activation-Induced Cytidine Deaminase Accelerates Clonal Evolution of BCR-ABL1-Driven B Cell Lineage Acute Lymphoblastic Leukemia. Blood 2009, 114: 181. DOI: 10.1182/blood.v114.22.181.181.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaAberrant AID expressionBCR-ABL1Lymphoblastic leukemiaB cellsBCR-ABL1 kinase domain mutationsB-cell lineage acute lymphoblastic leukemiaClonal evolutionTumor suppressor geneAberrant somatic hypermutationAID expressionB-cell lymphomaKinase domain mutationsGerminal center B cellsBone marrow cellsSuppressor geneBCR-ABL1 kinaseGC B cellsHazard ratioMedian survivalGenetic instabilityImatinib treatmentSomatic hypermutationB-cell lymphomagenesisCell lymphomaInducible 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 growth