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 pathwayMitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus
MacColl Garfinkel A, Mnatsakanyan N, Patel J, Wills A, Shteyman A, Smith P, Alavian K, Jonas E, Khokha M. Mitochondrial leak metabolism induces the Spemann-Mangold Organizer via Hif-1α in Xenopus. Developmental Cell 2023, 58: 2597-2613.e4. PMID: 37673063, PMCID: PMC10840693, DOI: 10.1016/j.devcel.2023.08.015.Peer-Reviewed Original ResearchConceptsSpemann-Mangold organizerATP productionMitochondrial respirationC subunit ringHIF-1αMitochondrial oxidative metabolismEmbryonic patterningCell fateATP synthaseC subunitVentral mesodermHIF-1α activationInstructive roleHypoxia-inducible factor-1αΒ-cateninGeneral mechanismXenopusFactor-1αRespirationMembrane leakOxidative metabolismMetabolismMesodermActivationOxygen consumptionDaam2 phosphorylation by CK2α negatively regulates Wnt activity during white matter development and injury
Wang C, Zuo Z, Jo J, Kim K, Madamba C, Ye Q, Jung S, Bellen H, Lee H. Daam2 phosphorylation by CK2α negatively regulates Wnt activity during white matter development and injury. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2304112120. PMID: 37607236, PMCID: PMC10469030, DOI: 10.1073/pnas.2304112120.Peer-Reviewed Original ResearchConceptsOL developmentWhite matter injuryCentral nervous systemWnt/β-cateninWhite matter developmentWnt activityNeonatal hypoxiaBehavioral recoveryMyelin repairMyelin restorationNervous systemProtective roleOligodendrocyte developmentΒ-cateninWnt pathwayInjuryMyelinationBiological mechanismsNew biological mechanismsEarly differentiationPhosphorylationDemyelinationPathwayβ-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 ProliferationDisturbed flow increases endothelial inflammation and permeability via a Frizzled-4-β-catenin-dependent pathway
Rickman M, Ghim M, Pang K, von Huelsen Rocha A, Drudi E, Sureda-Vives M, Ayoub N, Tajadura-Ortega V, George S, Weinberg P, Warboys C. Disturbed flow increases endothelial inflammation and permeability via a Frizzled-4-β-catenin-dependent pathway. Journal Of Cell Science 2023, 136: jcs260449. PMID: 36846872, PMCID: PMC10112981, DOI: 10.1242/jcs.260449.Peer-Reviewed Original ResearchConceptsEndothelial dysfunctionEndothelial cellsFrizzled-4Β-cateninCultured human aortic endothelial cellsR-spondinsHuman aortic endothelial cellsPro-inflammatory genesEndothelial paracellular permeabilityDisturbed flowAortic endothelial cellsCultured endothelial cellsRole of WntEndothelial inflammationAortic archEarly atherogenesisCanonical Wnt pathwayDysfunctionReduced expressionWnt5a signalingParacellular permeabilityWnt pathwayInhibitionKnockdownExpression
2022
Mink1 regulates spemann organizer cell fate in the xenopus gastrula via Hmga2
Colleluori V, Khokha M. Mink1 regulates spemann organizer cell fate in the xenopus gastrula via Hmga2. Developmental Biology 2022, 495: 42-53. PMID: 36572140, PMCID: PMC10116378, DOI: 10.1016/j.ydbio.2022.11.010.Peer-Reviewed Original ResearchConceptsSpemann organizerCell fateTranscription factorsMolecular mechanismsSerine/threonine kinaseLeft-right patterningProper heart developmentUnbiased proteomic approachArchitectural transcription factorPlausible molecular mechanismCHD candidate genesVertebrate embryosThreonine kinaseProteomic approachXenopus gastrulaCommon birth defectsHeart developmentCandidate genesCanonical WntOrganizer cellsSequencing studiesMINK1Critical effectorΒ-cateninHMGA2The origins of skin diversity: lessons from dermal fibroblasts
Myung P, Andl T, Atit R. The origins of skin diversity: lessons from dermal fibroblasts. Development 2022, 149 PMID: 36444877, PMCID: PMC10112899, DOI: 10.1242/dev.200298.Peer-Reviewed Original ResearchConceptsFibroblast subtypesSingle-cell levelWnt/β-cateninLineage diversificationHair follicle growthDermal developmentDermal fibroblastsExtraordinary diversityPositional signalsNatural variationFibroblast heterogeneityΒ-cateninDevelopmental originsDiverse groupMolecular heterogeneityCentral roleDiversityFibroblastsFollicle growthImportant roleLineagesSpeciesDiversificationDifferentiationOriginHistone H3 proline 16 hydroxylation regulates mammalian gene expression
Liu X, Wang J, Boyer J, Gong W, Zhao S, Xie L, Wu Q, Zhang C, Jain K, Guo Y, Rodriguez J, Li M, Uryu H, Liao C, Hu L, Zhou J, Shi X, Tsai Y, Yan Q, Luo W, Chen X, Strahl B, von Kriegsheim A, Zhang Q, Wang G, Baldwin A, Zhang Q. Histone H3 proline 16 hydroxylation regulates mammalian gene expression. Nature Genetics 2022, 54: 1721-1735. PMID: 36347944, PMCID: PMC9674084, DOI: 10.1038/s41588-022-01212-x.Peer-Reviewed Original ResearchConceptsPost-translational modificationsHistone post-translational modificationsMammalian gene expressionGene expressionHistone H3Mammalian cellsDNA-templated processesTranscriptome-wide analysisTarget gene expressionHydroxylation of prolineWnt/β-cateninChromatin recruitmentHistone codeTarget genesRegulatory marksLysine residuesDirect bindingTriple-negative breast cancerΒ-cateninResidues 16H3ExpressionH3K4me3TrimethylationGenomeKap-β2/Transportin mediates β-catenin nuclear transport in Wnt signaling
Hwang WY, Kostiuk V, González DP, Lusk CP, Khokha M. Kap-β2/Transportin mediates β-catenin nuclear transport in Wnt signaling. ELife 2022, 11: e70495. PMID: 36300792, PMCID: PMC9665845, DOI: 10.7554/elife.70495.Peer-Reviewed Original ResearchConceptsNuclear transport receptorsΒ-catenin nuclear transportNuclear transportΒ-cateninExcessive WntΒ-catenin nuclear importHeterologous model systemsΒ-catenin accumulatesPrimary embryonic axisNuclear transport machineryRan-dependent mannerNuclear localization signalTCF/LEF reporterPY-NLSNuclear importLocalization signalTransport machineryTransport receptorsResponsive genesEmbryonic developmentEmbryonic axisWnt signalingKey effectorsDirect bindingHuman diseasesIncreased Expression of LEF1 and β-Catenin in Invasive Micropapillary Carcinoma of the Breast is Associated With Lymphovascular Invasion and Lymph Node Metastasis
Dolezal D, Zhang X, Harigopal M. Increased Expression of LEF1 and β-Catenin in Invasive Micropapillary Carcinoma of the Breast is Associated With Lymphovascular Invasion and Lymph Node Metastasis. Applied Immunohistochemistry & Molecular Morphology 2022, 30: 557-565. PMID: 35960138, DOI: 10.1097/pai.0000000000001052.Peer-Reviewed Original ResearchConceptsInvasive micropapillary breast carcinomaLymph node metastasisLymphoid enhancer-binding factor 1Lymphovascular invasionNode metastasisNodal metastasisPrimary tumorΒ-cateninBreast tumorsRare breast cancer subtypeSmall tumor cell clustersLEF1 expressionMicropapillary breast carcinomaAggressive breast tumorsBasal-like carcinomasInvasive micropapillary carcinomaΒ-catenin expression levelsBreast cancer subtypesΒ-catenin expressionTumor cell clustersEnhancer-binding factor 1Disease relapseMicropapillary carcinomaBreast carcinomaHigh incidenceDysregulation of the Scribble/YAP/β‐catenin axis sustains the fibroinflammatory response in a PKHD1−/− mouse model of congenital hepatic fibrosis
Fabris L, Milani C, Fiorotto R, Mariotti V, Kaffe E, Seller B, Sonzogni A, Strazzabosco M, Cadamuro M. Dysregulation of the Scribble/YAP/β‐catenin axis sustains the fibroinflammatory response in a PKHD1−/− mouse model of congenital hepatic fibrosis. The FASEB Journal 2022, 36: e22364. PMID: 35593740, PMCID: PMC9150862, DOI: 10.1096/fj.202101924r.Peer-Reviewed Original ResearchConceptsYes-associated proteinPlanar cell polarityΒ-cateninΒ-catenin axisYAP nuclear importRole of ScribbleNuclear translocationYAP/TAZΒ-catenin signalingCell polarityNuclear importCyst cellsNuclear expressionScribble expressionΒ-catenin nuclear expressionConditional deletionGenetic defectsTissue growth factor expressionIntegrin β6Connective tissue growth factor expressionCyst growthExpressionCystic cholangiocytesMRNA levelsScribblesDecomposing a deterministic path to mesenchymal niche formation by two intersecting morphogen gradients
Qu R, Gupta K, Dong D, Jiang Y, Landa B, Saez C, Strickland G, Levinsohn J, Weng PL, Taketo MM, Kluger Y, Myung P. Decomposing a deterministic path to mesenchymal niche formation by two intersecting morphogen gradients. Developmental Cell 2022, 57: 1053-1067.e5. PMID: 35421372, PMCID: PMC9050909, DOI: 10.1016/j.devcel.2022.03.011.Peer-Reviewed Original ResearchConceptsMorphogen gradientsCell fate specificationWnt/β-cateninFate specificationShape tissuesOrgan formationCell fateDermal condensatesGenetic perturbationsNiche formationDifferentiation processSpatiotemporal patterningCell behaviorΒ-cateninMore intermediatesComputational approachProliferationMorphogenesisScRNAOrganogenesisShhKey componentProgenitorsCritical transitionDKK1
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 lesionsPIK3CA mutation in a case of CTNNB1 mutant sinonasal glomangiopericytoma
Hong C, Khan M, Sukys J, Prasad M, Erson-Omay EZ, Vining E, Omay SB. PIK3CA mutation in a case of CTNNB1 mutant sinonasal glomangiopericytoma. Molecular Case Studies 2021, 8: mcs.a006120. PMID: 34667073, PMCID: PMC8744496, DOI: 10.1101/mcs.a006120.Peer-Reviewed Original ResearchConceptsCase of glomangiopericytomaWhole-exome sequencingInstitutional review board-approved protocolTargeted medical therapyUnderwent surgical resectionPI3K/Akt/mTORWnt/β-cateninAkt/mTORPrimary sinonasal tumorSurgical resectionClinicopathologic characteristicsMedical therapyRare tumorPIK3CA mutationsSinonasal tumorsGlomangiopericytomaTumorsΒ-cateninSomatic mutationsComprehensive genetic characterizationGenomic characterizationMutationsConcurrent dysregulationResectionSinonasalPediatric Hepatocellular Adenomas
Pacheco MC, Torbenson MS, Wu TT, Kakar S, Jain D, Yeh MM. Pediatric Hepatocellular Adenomas. The American Journal Of Surgical Pathology 2021, 45: 1641-1647. PMID: 34148984, PMCID: PMC8608351, DOI: 10.1097/pas.0000000000001763.Peer-Reviewed Original ResearchConceptsHepatocellular adenomaPrepubescent groupPediatric patientsNonsyndromic groupΒ-cateninAdenoma subtypesImmunohistochemical staining profileHepatocellular adenoma subtypesPostpubescent groupClinical characteristicsUnclassified subtypeClinical historySyndromic groupsImmunohistochemical stainingPatientsType adenomasAdenomasSyndromeAge groupsLarger studyStaining profileSubtypesGreater percentageGroupLanguage search
2020
Expression of lymphoid enhancer-binding factor 1 in breast fibroepithelial lesions
Chen PH, Bossuyt V, Reisenbichler E. Expression of lymphoid enhancer-binding factor 1 in breast fibroepithelial lesions. Human Pathology 2020, 108: 68-75. PMID: 33245988, DOI: 10.1016/j.humpath.2020.11.009.Peer-Reviewed Original ResearchConceptsMalignant phyllodes tumorPhyllodes tumorBenign tumorsLymphoid enhancer-binding factor 1Fibroepithelial lesionsTissue microarrayEnhancer-binding factor 1LEF-1 expressionMalignant tumorsBorderline/malignant phyllodes tumorsΒ-cateninStromal componentsNuclear expressionWorld Health Organization criteriaMetastatic phyllodes tumorWnt/β-catenin pathway activationAlternative treatment optionBorderline phyllodes tumorWnt/β-catenin pathwayFactor 1Β-catenin pathway activationE-cadherin immunohistochemistryWnt/β-catenin signalingΒ-catenin pathwayNuclear β-catenin stainingDisrupted ER membrane protein complex-mediated topogenesis drives congenital neural crest defects
Marquez J, Criscione J, Charney RM, Prasad MS, Hwang WY, Mis EK, García-Castro MI, Khokha MK. Disrupted ER membrane protein complex-mediated topogenesis drives congenital neural crest defects. Journal Of Clinical Investigation 2020, 130: 813-826. PMID: 31904590, PMCID: PMC6994125, DOI: 10.1172/jci129308.Peer-Reviewed Original ResearchConceptsEndoplasmic reticulum (ER) membrane protein complexMultipass membrane proteinsNeural crest cellsMembrane proteinsHuman NCC developmentER membrane proteinsMembrane protein complexesCell-cell signalsMyriad of functionsNCC defectsNCC developmentProtein complexesUnbiased proteomicsXenopus modelTransmembrane proteinFunction allelesPatient phenotypesCrest cellsMolecular connectionNeural crestMolecular mechanismsBirth defectsPatient variantsEMC1Β-cateninRe-appraising the potential of naringin for natural, novel orthopedic biotherapies
Yu KE, Alder KD, Morris MT, Munger AM, Lee I, Cahill SV, Kwon HK, Back J, Lee FY. Re-appraising the potential of naringin for natural, novel orthopedic biotherapies. Therapeutic Advances In Musculoskeletal Disease 2020, 12: 1759720x20966135. PMID: 33343723, PMCID: PMC7727086, DOI: 10.1177/1759720x20966135.Peer-Reviewed Original ResearchBone morphogenetic proteinExtracellular signal-related kinase (ERK) pathwayRANK/RANKL interactionNumerous molecular pathwaysWnt/β-cateninBone resident cellsStem cell precursorsCellular differentiationKinase pathwayMorphogenetic proteinsPotential of naringinMolecular pathwaysΒ-cateninCellular mechanismsBone-preserving effectCommon musculoskeletal pathologiesEstrogen-sensitive tissuesOsteolytic bone diseaseCommon musculoskeletal conditionsMusculoskeletal developmentSystemic side effectsTreatment of osteoporosisDegenerative joint diseaseCell precursorsBone microenvironment
2019
An Underlying Mechanism of Dual Wnt Inhibition and AMPK Activation: Mitochondrial Uncouplers Masquerading as Wnt Inhibitors
Zhang W, Sviripa VM, Kril L, Yu T, Xie Y, Hubbard W, Sullivan P, Chen X, Zhan CG, Yang-Hartwich Y, Evers BM, Spear B, Gedaly R, Watt DS, Liu C. An Underlying Mechanism of Dual Wnt Inhibition and AMPK Activation: Mitochondrial Uncouplers Masquerading as Wnt Inhibitors. Journal Of Medicinal Chemistry 2019, 62: 11348-11358. PMID: 31774672, PMCID: PMC7560992, DOI: 10.1021/acs.jmedchem.9b01685.Peer-Reviewed Original ResearchLgr5 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
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