2023
Repurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies
Cosgun K, Robinson M, Oulghazi S, Xu L, Xiao G, Chan L, Lee J, Kume K, Leveille E, Arce D, Khanduja D, Feldhahn N, Song J, Chan W, Chen J, Taketo M, Schjerven H, Jellusova J, Kothari S, Davids M, Müschen M. Repurposing GSK3B Small Molecule Inhibitors for Refractory Lymphoid Malignancies. Blood 2023, 142: 2818. DOI: 10.1182/blood-2023-190522.Peer-Reviewed Original ResearchFavorable safety profileSmall molecule inhibitorsT-lymphoid malignancyΒ-catenin degradationLymphoid malignanciesΒ-cateninInteractome studiesSafety profileClinical trialsMolecule inhibitorsLow nanomolar concentrationsΒ-catenin accumulationSolid tumorsRefractory B-cell malignanciesCell deathPK/PD profilesZinc finger proteinRefractory lymphoid malignanciesChIP-seq analysisPhase 2 trialMYC target genesT-cell lymphomaColony formationRapid nuclear accumulationWnt/β-catenin pathway
2015
IFITM3 (CD225) Links the B Cell Antigen CD19 to PI3K-AKT Signaling in Human ALL Cells
Lee J, Geng H, Chen Z, Eugene P, Klemm L, Bailey C, Muschen M. IFITM3 (CD225) Links the B Cell Antigen CD19 to PI3K-AKT Signaling in Human ALL Cells. Blood 2015, 126: 1325. DOI: 10.1182/blood.v126.23.1325.1325.Peer-Reviewed Original ResearchTime of diagnosisPI3K-Akt signalingPI3K-AktHuman preSurface expressionAgonistic antibodiesB-cell antigen CD19Patient-derived preRelapse-free survivalMRNA levelsChimeric antigen receptorMedian expression levelPI3K p110δSurface receptorsColony formation capacityMRD statusInduction chemotherapyImmunotherapy approachesAntigen CD19Cell cycle arrestCell receptor complexClinical trialsCD19 expressionHigh riskB cell progenitorsSelf-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
2013
Identification Of BCL6 As a Therapeutic Target In MLL-Rearranged ALL
Hurtz C, Geng H, Ballabio E, Xiao G, Ng C, Masouleh B, Willman C, Armstrong S, Milne T, Melnick A, Muschen M. Identification Of BCL6 As a Therapeutic Target In MLL-Rearranged ALL. Blood 2013, 122: 72. DOI: 10.1182/blood.v122.21.72.72.Peer-Reviewed Original ResearchDiffuse large B-cell lymphomaFunction of Bcl6White blood countPoor clinical outcomeAcute lymphoblastic leukemiaMinimal residual diseaseClinical outcomesMLL-AF4Clinical trialsBCL6 levelsPositive minimal residual diseasePharmacological inhibitionHigher white blood countExpression levelsLarge B-cell lymphomaAberrant expressionChemotherapy drugs vincristineBCL6 protein levelsTime of diagnosisWorse clinical outcomesBCL6 expressionRelapse-free survivalProtein levelsPediatric clinical trialsB-cell lymphomaOncogene-Induced DNA Repair Defects Promote PARP1-Mediated “Dual Synthetic Lethality” To Eradicate Quiescent and Proliferating Leukemia Stem and Progenitor Cells
Nieborowska-Skorska M, Slupianek A, Hoser G, Bolton-Gillespie E, Tulin A, Cerny-Reiterer S, Valent P, Muschen M, Sykes S, Skorski T. Oncogene-Induced DNA Repair Defects Promote PARP1-Mediated “Dual Synthetic Lethality” To Eradicate Quiescent and Proliferating Leukemia Stem and Progenitor Cells. Blood 2013, 122: 810. DOI: 10.1182/blood.v122.21.810.810.Peer-Reviewed Original ResearchQuiescent leukemia stem cellsLeukemia progenitor cellsLeukemia stem cellsImatinib-naïveLeukemia cellsAML1-ETOBCR-ABL1PARP1 inhibitorsProgenitor cellsNormal cellsAnti-leukemia effectPositive AML cellsBCR-ABL1 T315I mutationInhibited colony formationAnti-proliferative effectsPARP inhibitor olaparibStem cellsModest inhibitory effectInhibition of PARPPeripheral bloodDisease burdenBone marrow nicheClinical trialsAML cellsT315I mutation
2012
Integrative Analysis of Ikaros-Dependent Changes of Transcriptional Regulation and Tyrosine Phosphorylation Events in Ph+ ALL
Geng H, Nahar R, Ramezani-Rad P, Chen Z, Tyner J, Chang B, Titz B, Buchner M, Hurtz C, Graeber T, Druker B, Paietta E, Melnick A, Willman C, Carroll W, Muschen M. Integrative Analysis of Ikaros-Dependent Changes of Transcriptional Regulation and Tyrosine Phosphorylation Events in Ph+ ALL. Blood 2012, 120: 528. DOI: 10.1182/blood.v120.21.528.528.Peer-Reviewed Original ResearchGene expression changesTyrosine phosphorylation eventsExpression changesTarget genesPhosphorylation eventsIkaros functionTyrosine phosphorylationClinical trial fundingTumor suppressorAbility of IkarosDependent survival signalsTyrosine kinase LckClinical trialsSet of genesBCL6 target genesComprehensive gene expression analysisChIP-seq dataIkaros transcription factorGene expression analysisRole of IkarosGene expression microarraysTrial fundingBristol-Myers SquibbClinical outcomesFurther biochemistryIdentification of FoxM1 As Therapeutic Target in TKI-Resistant Ph+ ALL
Buchner M, Klemm L, Zhengshan C, Geng H, Muschen M. Identification of FoxM1 As Therapeutic Target in TKI-Resistant Ph+ ALL. Blood 2012, 120: 874. DOI: 10.1182/blood.v120.21.874.874.Peer-Reviewed Original ResearchB cell precursorsLymphoblastic leukemiaTherapeutic targetPhiladelphia chromosome-positive acute lymphoblastic leukemiaPositive acute lymphoblastic leukemiaARF peptidesCell precursorsTreatment of TKIMajority of patientsTime of diagnosisAcute lymphoblastic leukemiaPatient-derived xenograftsValid therapeutic targetEffects of TKIsPotential therapeutic agentForkhead box transcription factor familyCell cycleSuperoxide dismutase expressionG0/G1Thiostrepton treatmentTKI treatmentPoor outcomeCombination therapyFl miceClinical trials