2024
Identification of High-Efficiency β-Catenin Protein Degradation As Critical Vulnerability in B-Cell Malignancies
Cosgun K, Robinson M, Agadzhanian N, Cheng Z, Oulghazi S, Berning P, Fonseca-Arce D, Kume K, Fontaine J, Chan L, Lee J, Yu F, Qian Z, Song J, Chan W, Chen J, Taketo M, Schjerven H, Müschen M. Identification of High-Efficiency β-Catenin Protein Degradation As Critical Vulnerability in B-Cell Malignancies. Blood 2024, 144: 4125-4125. DOI: 10.1182/blood-2024-208125.Peer-Reviewed Original ResearchProtein degradation pathwaysB-ALL cellsProtein degradationRepression of MYCTranscriptional activity of MYCCell deathAcute cell deathLoss of colony formationChIP-seq analysisActive enhancer marksB-cell malignanciesSuper-enhancer regionsActivation of MYCIkaros transcription factorB-lymphoid cellsCell linesB cell identityDefective protein degradationB-cateninNon-lymphoid cell linesDegradation pathwayMantle cell lymphomaProtein levelsB-ALLChIP-seqDependence of lymphopoiesis on efficient β-catenin degradation
Cosgun K, Jumaa H, Robinson M, Klemm L, Oulghazi S, Fonseca-Arce D, Xu L, Xiao G, Khanduja D, Chan L, Lee J, Kume K, Song J, Chan W, Chen J, Taketo M, Kothari S. Dependence of lymphopoiesis on efficient β-catenin degradation. The Journal Of Immunology 2024, 212: 1195_4936-1195_4936. DOI: 10.4049/jimmunol.212.supp.1195.4936.Peer-Reviewed Original ResearchIkaros zinc fingersLymphoid cellsB-cateninChIP-seq analysisSuppression of MYC expressionRegulate lineage specificationInduce cell deathConstitutively low levelsDeletion of ApcChIP-seqTcf factorsZinc fingerProteasomal degradationBinding motifNucleosome remodelingDestruction complexSpecific genesWnt/b-catenin pathwayLineage specificationCell deathMYC expressionSuperenhancersLymphoid developmentEpithelial lineageEpithelial cells
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 pathwayDynamic Recruitment of Inhibitory Complexes Controls Oncogenic Signaling in B-Cell Malignancies
Sun R, Lee J, Robinson M, Kume K, Ma N, Cosgun K, Chan L, Antoshkina I, Khanduja D, Leveille E, Katz S, Chen J, Paietta E, Vaidehi N, Müschen M. Dynamic Recruitment of Inhibitory Complexes Controls Oncogenic Signaling in B-Cell Malignancies. Blood 2023, 142: 719. DOI: 10.1182/blood-2023-189742.Peer-Reviewed Original ResearchB-cell malignanciesB-cell lymphomaHigher serum levelsMature B-cell lymphomasSoluble CD25Serum levelsOncogenic signalingMouse modelB cellsAggressive B-cell lymphomasAcceleration of diseaseActivation of inhibitoryPoor clinical outcomeCD25 surface expressionB cell subsetsRole of CD25Patient-derived xenograftsB cell populationsB-cell receptor signalingB-cell leukemiaGenetic mouse modelsKnockin mouse modelCell deathMature B cell populationClinical outcomes