2020
IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells
Lee J, Robinson ME, Ma N, Artadji D, Ahmed MA, Xiao G, Sadras T, Deb G, Winchester J, Cosgun KN, Geng H, Chan LN, Kume K, Miettinen TP, Zhang Y, Nix MA, Klemm L, Chen CW, Chen J, Khairnar V, Wiita AP, Thomas-Tikhonenko A, Farzan M, Jung JU, Weinstock DM, Manalis SR, Diamond MS, Vaidehi N, Müschen M. IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells. Nature 2020, 588: 491-497. PMID: 33149299, PMCID: PMC8087162, DOI: 10.1038/s41586-020-2884-6.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntigens, CD19B-LymphocytesCell Transformation, NeoplasticFemaleGerminal CenterHumansIntegrinsMembrane MicrodomainsMembrane ProteinsMiceMice, Inbred C57BLMice, Inbred NODModels, MolecularPhosphatidylinositol 3-KinasesPhosphatidylinositol PhosphatesPhosphorylationReceptors, Antigen, B-CellRNA-Binding ProteinsSignal TransductionConceptsPI3KCell leukemiaAntiviral effector functionsAntigen-specific antibodiesInterferon-induced transmembrane proteinsIFITM3 functionDevelopment of leukemiaCell surfacePoor outcomeOncogenic PI3KClinical cohortEffector functionsGerminal centersMouse modelB cellsExpression of IFITM3Malignant transformationAccumulation of PIP3PI3K signalsCell receptorNormal numbersLeukemiaDefective expressionEndosomal proteinIFITM3
2018
Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells
Sullivan-Reed K, Bolton-Gillespie E, Dasgupta Y, Langer S, Siciliano M, Nieborowska-Skorska M, Hanamshet K, Belyaeva EA, Bernhardy AJ, Lee J, Moore M, Zhao H, Valent P, Matlawska-Wasowska K, Müschen M, Bhatia S, Bhatia R, Johnson N, Wasik MA, Mazin AV, Skorski T. Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells. Cell Reports 2018, 23: 3127-3136. PMID: 29898385, PMCID: PMC6082171, DOI: 10.1016/j.celrep.2018.05.034.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBRCA1 ProteinBRCA2 ProteinDNA RepairFemaleFusion Proteins, bcr-ablHomologous RecombinationHumansImatinib MesylateKaplan-Meier EstimateLeukemia, Myeloid, AcuteMaleMiceMice, Inbred NODMice, KnockoutPhthalazinesPiperazinesPoly (ADP-Ribose) Polymerase-1Rad52 DNA Repair and Recombination ProteinSynthetic Lethal MutationsTumor Suppressor p53-Binding Protein 1ConceptsTumor cellsBRCA-deficient tumor cellsSimultaneous targetingBRCA-deficient tumorsClinical trialsProlonged latencyImmunodeficient miceTherapeutic outcomesBRCA1-deficient tumorsPARP inhibitorsBRCA-deficient cellsMinimal toxicitySynergistic activitySynthetic lethal effectTumorsNormal cellsPARPiSynthetic lethalityInhibitorsLethal effectsCellsDominant negative mutantSynergistic accumulationMalignancyTargetingB-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies
Xiao G, Chan LN, Klemm L, Braas D, Chen Z, Geng H, Zhang QC, Aghajanirefah A, Cosgun KN, Sadras T, Lee J, Mirzapoiazova T, Salgia R, Ernst T, Hochhaus A, Jumaa H, Jiang X, Weinstock DM, Graeber TG, Müschen M. B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies. Cell 2018, 173: 470-484.e18. PMID: 29551267, PMCID: PMC6284818, DOI: 10.1016/j.cell.2018.02.048.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsB-LymphocytesCarbonCell Line, TumorCell SurvivalGlucoseGlucosephosphate DehydrogenaseGlycolysisHumansIkaros Transcription FactorMiceMice, Inbred C57BLMice, Inbred NODOxidative StressPAX5 Transcription FactorPentose Phosphate PathwayPrecursor Cell Lymphoblastic Leukemia-LymphomaProtein Phosphatase 2Proto-Oncogene Proteins c-bcl-2Transcription, GeneticConceptsPentose phosphate pathwayCarbon utilizationSerine/threonine protein phosphatase 2AB-cell transcription factor PAX5Transcription factor Pax5Favor of glycolysisSmall molecule inhibitionPhosphatase 2ATranscriptional repressionRedox homeostasisOncogenic transformationTumor suppressorMolecule inhibitionPP2AGenetic studiesPhosphate pathwayB cell activationEssential roleB-cell malignanciesCell malignanciesB cellsAntioxidant protectionOxidative stressB-cell tumorsCell activation
2015
Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia
Chen Z, Shojaee S, Buchner M, Geng H, Lee JW, Klemm L, Titz B, Graeber TG, Park E, Tan YX, Satterthwaite A, Paietta E, Hunger SP, Willman CL, Melnick A, Loh ML, Jung JU, Coligan JE, Bolland S, Mak TW, Limnander A, Jumaa H, Reth M, Weiss A, Lowell CA, Müschen M. Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia. Nature 2015, 521: 357-361. PMID: 25799995, PMCID: PMC4441554, DOI: 10.1038/nature14231.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAnimalsAntigens, CDB-LymphocytesCell DeathCell Line, TumorCell Transformation, NeoplasticDisease Models, AnimalDrug Resistance, NeoplasmEnzyme ActivationFemaleFusion Proteins, bcr-ablGene DeletionHumansInositol Polyphosphate 5-PhosphatasesIntracellular Signaling Peptides and ProteinsMiceMice, Inbred NODMice, SCIDPhosphatidylinositol-3,4,5-Trisphosphate 5-PhosphatasesPhosphoric Monoester HydrolasesPlatelet Endothelial Cell Adhesion Molecule-1Precursor Cell Lymphoblastic Leukemia-LymphomaPrecursor Cells, B-LymphoidProtein Tyrosine Phosphatase, Non-Receptor Type 6Protein-Tyrosine KinasesReceptors, Antigen, B-CellReceptors, ImmunologicSignal TransductionSyk KinaseTyrosineXenograft Model Antitumor Assays