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
2015
Targeted Activation of B Cell Autoimmunity Checkpoints in Acute Lymphoblastic Leukemia
Chen Z, Geng H, Lowell C, Weiss A, Hunger S, Melnick A, Muschen M. Targeted Activation of B Cell Autoimmunity Checkpoints in Acute Lymphoblastic Leukemia. Blood 2015, 126: 3716. DOI: 10.1182/blood.v126.23.3716.3716.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsB cell receptorAcute lymphoblastic leukemiaPre-BCR signalingB cellsB cell selectionLymphoblastic leukemiaBCR-ABL1Autoreactive B cell receptorsCell deathPre-B-cell originAcute lymphoblastic leukemia cellsCurrent therapy approachesLeukemia cellsWorse clinical outcomesSelf-reactive B cellsNegative B cell selectionPotent tyrosine kinase inhibitorLymphoblastic leukemia cellsNovel small molecule inhibitorTypes of cancerUbiquitous self-antigenClinical outcomesIncremental increasePoor outcomeIdentification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia
Buchner M, Park E, Geng H, Klemm L, Flach J, Passegué E, Schjerven H, Melnick A, Paietta E, Kopanja D, Raychaudhuri P, Müschen M. Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia. Nature Communications 2015, 6: 6471. PMID: 25753524, PMCID: PMC4366523, DOI: 10.1038/ncomms7471.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsAntineoplastic AgentsB-LymphocytesCell ProliferationCell SurvivalChildClinical Trials as TopicCyclin-Dependent Kinase Inhibitor p16Drug Resistance, NeoplasmForkhead Box Protein M1Forkhead Box Protein O3Forkhead Transcription FactorsGene Expression Regulation, LeukemicHumansMicePeptidesPrecursor Cell Lymphoblastic Leukemia-LymphomaSignal TransductionSurvival AnalysisThiostreptonXenograft Model Antitumor AssaysConceptsAcute lymphoblastic leukemiaLymphoblastic leukemiaTherapeutic targetB-cell lineage acute lymphoblastic leukemiaFOXM1 levelsAggressive clinical coursePre-B cell receptor checkpointNovel therapeutic targetB cell populationsNormal B cell populationsClinical coursePoor outcomeCure rateNormal B cell developmentFOXM1 inhibitionB cell developmentDrug resistanceFoxm1 deletionFOXM1Colony formationPatientsLeukemiaCell survivalPrognosisTranscriptional inactivation
2012
Identification 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 trialsSuppressor of Cytokine Signaling (SOCS) Molecules Are Critical to Balance Oncogenic Signaling Strength in Ph+ ALL.
Chen Z, Geng H, Klemm L, Buchner M, Hemati K, Shojaee S, Alexander W, Carroll W, Willman C, Muschen M. Suppressor of Cytokine Signaling (SOCS) Molecules Are Critical to Balance Oncogenic Signaling Strength in Ph+ ALL. Blood 2012, 120: 2563. DOI: 10.1182/blood.v120.21.2563.2563.Peer-Reviewed Original ResearchBCR-ABL1Leukemia cellsTherapeutic targetSurvival rateP-STAT5Acute lymphoblastic leukemia cellsFree survival rateOverall survival rateHigh expression levelsG0/G1 cell cycle arrestRole of SOCS2Course of diseaseMRNA levelsAdditional therapeutic targetsNOD-SCID miceInducible deletionG1 cell cycle arrestLymphoblastic leukemia cellsExpression levelsCellular senescenceCOG trialsLeukemia regressionExpression of SOCS2Poor outcomeJAK/STAT pathway