Featured Publications
Novel PIK3CD mutations affecting N-terminal residues of p110δ cause activated PI3Kδ syndrome (APDS) in humans
Takeda AJ, Zhang Y, Dornan GL, Siempelkamp BD, Jenkins ML, Matthews HF, McElwee JJ, Bi W, Seeborg FO, Su HC, Burke JE, Lucas CL. Novel PIK3CD mutations affecting N-terminal residues of p110δ cause activated PI3Kδ syndrome (APDS) in humans. Journal Of Allergy And Clinical Immunology 2017, 140: 1152-1156.e10. PMID: 28414062, PMCID: PMC5632585, DOI: 10.1016/j.jaci.2017.03.026.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultChildClass I Phosphatidylinositol 3-KinasesFemaleHumansImmunologic Deficiency SyndromesMaleMutationDominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency
Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nature Immunology 2013, 15: 88-97. PMID: 24165795, PMCID: PMC4209962, DOI: 10.1038/ni.2771.Peer-Reviewed Original ResearchMeSH KeywordsAntibiotics, AntineoplasticCell DifferentiationCells, CulturedCellular SenescenceClass I Phosphatidylinositol 3-KinasesCytomegalovirus InfectionsEpstein-Barr Virus InfectionsFemaleGenes, DominantGerm-Line MutationHumansImmunoblottingImmunologic Deficiency SyndromesMalePedigreePhosphatidylinositol 3-KinasesPhosphorylationProto-Oncogene Proteins c-aktSirolimusT-LymphocytesTOR Serine-Threonine KinasesViremia
2023
PI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond
Cant A, Chandra A, Munro E, Rao V, Lucas C. PI3Kδ Pathway Dysregulation and Unique Features of Its Inhibition by Leniolisib in Activated PI3Kδ Syndrome and Beyond. The Journal Of Allergy And Clinical Immunology In Practice 2023, 12: 69-78. PMID: 37777067, PMCID: PMC10872751, DOI: 10.1016/j.jaip.2023.09.016.Peer-Reviewed Original ResearchMeSH KeywordsClass I Phosphatidylinositol 3-KinasesHumansPhosphatidylinositol 3-KinasePhosphatidylinositol 3-KinasesPyrimidinesConceptsPI3Kδ inhibitorsActivated PI3Kδ SyndromeImmune cell developmentPI3Kδ syndromeSpecific inhibitory propertiesAdverse eventsTreatment optionsPI3Kδ activityHematological malignanciesPathway dysregulationInborn errorsDrug mechanismsGenetic hyperactivationLeniolisibSyndromeΔ isoformsCell developmentInhibitorsInhibitory propertiesΓ isoformsColitisNeutropeniaTolerabilityMalignancyHepatotoxicity
2021
Infections in activated PI3K delta syndrome (APDS)
Brodsky NN, Lucas CL. Infections in activated PI3K delta syndrome (APDS). Current Opinion In Immunology 2021, 72: 146-157. PMID: 34052541, DOI: 10.1016/j.coi.2021.04.010.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsPI3K delta syndromeHematopoietic stem cell transplantAnti-microbial prophylaxisPI3K-delta syndromeStem cell transplantSenescent T cellsSpectrum of infectionsAdaptive immune functionAutosomal dominant disorderCell transplantImmune defectsImmunoglobulin replacementRecurrent infectionsImmunomodulatory agentsTherapy optionsT cellsImmune functionInfection susceptibilityInborn errorsDominant disorderInfectionLymphadenopathyPatientsFunction mutationsImmunodeficiency
2020
Editorial: Human Disorders of PI3K Biology
Lucas CL, Tangye SG. Editorial: Human Disorders of PI3K Biology. Frontiers In Immunology 2020, 11: 617464. PMID: 33329612, PMCID: PMC7732539, DOI: 10.3389/fimmu.2020.617464.Peer-Reviewed Original ResearchClass I Phosphatidylinositol 3-KinasesHumansPhosphatidylinositol 3-KinasesPrimary Immunodeficiency Diseases
2017
Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisib
Rao VK, Webster S, Dalm VASH, Šedivá A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, Joshi AD, de Buck S, Doucet J, Guerini D, Kalis C, Pylvaenaeinen I, Soldermann N, Kashyap A, Uzel G, Lenardo MJ, Patel DD, Lucas CL, Burkhart C. Effective “activated PI3Kδ syndrome”–targeted therapy with the PI3Kδ inhibitor leniolisib. Blood 2017, 130: 2307-2316. PMID: 28972011, PMCID: PMC5701526, DOI: 10.1182/blood-2017-08-801191.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsChemokinesChildChild, PreschoolClass I Phosphatidylinositol 3-KinasesDemographyDose-Response Relationship, DrugFemaleHumansImmunoglobulin MImmunologic Deficiency SyndromesInfantLymph NodesLymphocyte ActivationMaleMolecular Targeted TherapyMutationOrgan SizePhenotypePrimary Immunodeficiency DiseasesProtein Kinase InhibitorsPyridinesPyrimidinesRatsSpleenT-LymphocytesTOR Serine-Threonine KinasesTransfectionConceptsImmune dysregulationT cellsB cellsElevated serum immunoglobulin MPI3K/Akt pathway activityDose-escalation studyLymph node sizeSenescent T cellsWeeks of treatmentDose-dependent suppressionTransitional B cellsTumor necrosis factorDose-dependent reductionPrecision medicine therapiesSerum immunoglobulin MNaive B cellsT cell blastsAkt pathway activityAPDS patientsPI3Kδ pathwayInflammatory markersPD-1Clinical parametersSpleen volumeImmune deficiencyConformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1
Dornan GL, Siempelkamp BD, Jenkins ML, Vadas O, Lucas CL, Burke JE. Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 1982-1987. PMID: 28167755, PMCID: PMC5338455, DOI: 10.1073/pnas.1617244114.Peer-Reviewed Original ResearchMeSH KeywordsCatalytic DomainCell MembraneClass I Phosphatidylinositol 3-KinasesClass Ia Phosphatidylinositol 3-KinaseEnzyme AssaysEnzyme InhibitorsGain of Function MutationHumansImmunologic Deficiency SyndromesMass SpectrometryModels, MolecularPhenotypePhosphatidylinositol 3-KinasesPrimary Immunodeficiency DiseasesProtein ConformationPurinesQuinazolinonesRandomized Controlled Trials as TopicSequence DeletionConceptsRegulatory subunitCatalytic subunitClass IA catalytic subunitsHydrogen-deuterium exchange mass spectrometryOncogenic mutationsP85 regulatory subunitExchange mass spectrometryClass IA phosphoinositideP85α regulatory subunitPI3K delta syndromeCSH2 domainMolecular basisP110δ catalytic subunitMolecular mechanismsBiochemical assaysSubunits