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 pathwayβ-catenin engages IKZF factors to control lymphopoiesis
Cosgun K, Jumaa H, Robinson M, Xu L, Xiao G, Arce D, Khanduja D, Chan L, Lee J, Schjerven H, Jellusova J, Müschen M. β-catenin engages IKZF factors to control lymphopoiesis. The Journal Of Immunology 2023, 210: 65.09-65.09. DOI: 10.4049/jimmunol.210.supp.65.09.Peer-Reviewed Original ResearchΒ-cateninZinc finger transcription factorFinger transcription factorDramatic nuclear accumulationGSK3β-dependent phosphorylationT cell signalingT cell developmentTCF factorsRepressive complexesTranscriptional controlEnhancer clusterInteractome studiesTranscriptional activationΒ-catenin activationCommon oncogenic driversInhibition of GSK3βTranscription factorsNegative regulationMesenchymal lineagesNuclear accumulationCell deathMYCT-lymphoid malignancyΒ-catenin expressionPromotes Proliferation
2021
Beta-Catenin Forms Repressive Complexes with Ikzf1 and Ikzf3 to Orchestrate Tumor-Suppression in B-Cell Malignancies
Cosgun K, Robinson M, Chan L, Hur M, Leveille E, Song J, Chan W, Müschen M. Beta-Catenin Forms Repressive Complexes with Ikzf1 and Ikzf3 to Orchestrate Tumor-Suppression in B-Cell Malignancies. Blood 2021, 138: 29. DOI: 10.1182/blood-2021-148597.Peer-Reviewed Original ResearchB-cell malignanciesΒ-catenin activationΒ-cateninOncogenic Wnt/β-catenin signalingMalignant B-lymphoid cellsGenetic deletionRefractory B-ALLTranscriptional repressionB-cell lymphomaTumor suppressionWnt/β-catenin signalingΒ-catenin/TCF complexMature B-cell malignanciesB-lymphoid cellsCancer cell linesΒ-catenin signalingClonal fitnessOverall survivalLeukemia burdenNSG miceB-ALLCell cycle arrestNuclear β-cateninPan-cancer analysisFrequent lesions
2019
Lgr5 Functions As a Critical Negative Regulator of Wnt/β-Catenin Signaling and Is Essential for B-Lymphopoiesis and Malignant B-Cell Transformation
Cosgun K, Deb G, Yang X, Xiao G, Sadras T, Lee J, Chan L, Kume K, Yang L, Geng H, Chan J, Song J, Jumaa H, Polson A, Clevers H, Müschen M. Lgr5 Functions As a Critical Negative Regulator of Wnt/β-Catenin Signaling and Is Essential for B-Lymphopoiesis and Malignant B-Cell Transformation. Blood 2019, 134: 748. DOI: 10.1182/blood-2019-127263.Peer-Reviewed Original ResearchB-cell lineage acute lymphoblastic leukemiaWnt/β-catenin signalingΒ-catenin signalingNuclear β-cateninAntibody-drug conjugatesB cell developmentB cell survivalΒ-cateninB lymphopoiesisFunction of LGR5Median mRNA levelsTime of diagnosisPoor clinical outcomeRole of LGR5Acute lymphoblastic leukemiaB-cell lymphomaLeukemia initiating cellsWnt/β-cateninHigh surface expressionMalignant B-cell transformationCell linesB cell precursorsTypes of cancerHuman colon cancer cell linesB-cell lineage
2018
Lgr5 Enables Positive B-Cell Selection and Tumor-Initiation in B-Cell Malignancies
Cosgun K, Deb G, Yang X, Xiao G, Sadras T, Auer F, Lee J, Abarientos A, Mangolini M, Aghajanirefah A, Geng H, Jumaa H, Polson A, Clevers H, Muschen M. Lgr5 Enables Positive B-Cell Selection and Tumor-Initiation in B-Cell Malignancies. Blood 2018, 132: 547. DOI: 10.1182/blood-2018-99-116956.Peer-Reviewed Original ResearchB-cell malignanciesB-cell lineageAntibody-drug conjugatesLeukemia-initiating cellsTransplant recipientsB-ALLSurface expressionCancer stem cell markersWorse overall survivalMature B cell poolPoor clinical outcomeSingle-agent treatmentΒ-cateninB cell poolB cell selectionStem cell markersΒ-catenin activationΒ-catenin target genesLGR5 overexpressionLIC frequencyOverall survivalLeukemia burdenClinical outcomesEnvironmental antigensRecipient mice
2010
WNT/β-Catenin Signaling in Leukemia
Müschen M. WNT/β-Catenin Signaling in Leukemia. 2010, 129-142. DOI: 10.1007/978-1-4419-8023-6_6.Peer-Reviewed Original ResearchWnt/β-catenin signalingΒ-catenin signalingLeukemia stem cellsLeukemia-initiating cellsStem cellsRelapse of leukemiaMajor clinical problemWnt/β-cateninNovel therapy approachesActive Wnt/β-catenin signalingNormal hematopoiesisTreatment of leukemiaLeukemic cloneClinical problemLeukemia subtypesLeukemiaHematopoietic stem cellsNatural historyDrug resistanceMalignant outgrowthMultiple hematopoietic lineagesProgenitor cellsΒ-cateninTherapy approachesMyeloid progenitorsOvercoming Drug Resistance In Acute Lymphoblastic Leukemia by Inhibition of CBP/γ-Catenin
Jiang E, Park E, Nguyen C, Yoon J, Hsieh Y, Loh M, Muschen M, Kahn M, Kim Y. Overcoming Drug Resistance In Acute Lymphoblastic Leukemia by Inhibition of CBP/γ-Catenin. Blood 2010, 116: 3264. DOI: 10.1182/blood.v116.21.3264.3264.Peer-Reviewed Original ResearchICG-001 treatmentMedian survival timeICG-001Β-cateninΓ-cateninDose-dependent downregulationSaline control groupAcute lymphoblastic leukemiaSmall molecule specific inhibitorNOD/SCIDReduction of survivinΒ-catenin siRNAReal-time RT-PCRDownregulation of survivinΒ-catenin expressionDecrease of survivinOvercoming Drug ResistanceTime RT-PCRWestern blot analysisPoor prognosisLymphoblastic leukemiaColon cancer cellsSurvival timeShRNA controlXenograft cells
2007
Preclinical Evaluation of CBP/β-catenin Inhibition as a New Strategy for Drug Resistant Acute Lymphoblastic Leukemia.
Kim Y, Park E, Lorentzen C, De La Torre B, Hsieh Y, Whang H, Klemm L, Nguyen C, McMillan M, Teo J, Muschen M, Kahn M. Preclinical Evaluation of CBP/β-catenin Inhibition as a New Strategy for Drug Resistant Acute Lymphoblastic Leukemia. Blood 2007, 110: 1596. DOI: 10.1182/blood.v110.11.1596.1596.Peer-Reviewed Original ResearchAcute lymphoblastic leukemiaMedian survival timeStandard chemotherapyICG-001Expression of survivinLymphoblastic leukemiaLeukemia cellsXenograft modelDrug-resistant acute lymphoblastic leukemiaSmall molecule inhibitor ICG-001NOD/SCID xenograft modelHuman preCBP/β-cateninPromising therapeutic principleBlood count analysisSCID xenograft modelSurvival of miceNovel therapeutic optionsNew treatment modalitiesΒ-cateninDrug-resistant leukemia cellsΒ-catenin inhibitionHigh death rateResistant leukemia cellsSurvivin mRNA expression