Featured Publications
ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control
Gao Y, Zimmer J, Vasic R, Liu C, Gbyli R, Zheng S, Patel A, Liu W, Qi Z, Li Y, Nelakanti R, Song Y, Biancon G, Xiao A, Slavoff S, Kibbey R, Flavell R, Simon M, Tebaldi T, Li H, Halene S. ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control. Cell Reports 2023, 42: 113163. PMID: 37742191, PMCID: PMC10636609, DOI: 10.1016/j.celrep.2023.113163.Peer-Reviewed Original ResearchMeSH KeywordsAlkB Homolog 5, RNA DemethylaseAnimalsEnergy MetabolismHematopoietic Stem CellsHumansLeukemiaMiceRNARNA StabilityConceptsAlkB homolog 5Post-transcriptional regulatory mechanismsHematopoietic stemNumerous cellular processesProgenitor cell fitnessEnergy metabolismMitochondrial ATP productionMethyladenosine (m<sup>6</sup>A) RNA modificationTricarboxylic acid cycleCell energy metabolismHuman hematopoietic cellsMitochondrial energy productionCell fitnessCellular processesRNA modificationsRNA methylationRegulatory mechanismsEnzyme transcriptsATP productionHomolog 5Acid cycleΑ-ketoglutarateHematopoietic cellsMessenger RNAΑ-KGCombined liver–cytokine humanization comes to the rescue of circulating human red blood cells
Song Y, Shan L, Gbyli R, Liu W, Strowig T, Patel A, Fu X, Wang X, Xu ML, Gao Y, Qin A, Bruscia EM, Tebaldi T, Biancon G, Mamillapalli P, Urbonas D, Eynon E, Gonzalez DG, Chen J, Krause DS, Alderman J, Halene S, Flavell RA. Combined liver–cytokine humanization comes to the rescue of circulating human red blood cells. Science 2021, 371: 1019-1025. PMID: 33674488, PMCID: PMC8292008, DOI: 10.1126/science.abe2485.Peer-Reviewed Original ResearchConceptsRed blood cellsBlood cellsHuman sickle cell diseaseSickle cell diseaseImmunodeficient murine modelKupffer cell densityBone marrow failureMISTRG miceIntrasplenic injectionSCD pathologyCell diseaseMurine modelComplement C3RBC survivalVivo modelHuman cytokinesPreclinical testingHematopoietic stem cellsHuman red blood cellsMarrow failureFumarylacetoacetate hydrolase geneHuman erythropoiesisHuman liverHuman hepatocytesMicem6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development
Gao Y, Vasic R, Song Y, Teng R, Liu C, Gbyli R, Biancon G, Nelakanti R, Lobben K, Kudo E, Liu W, Ardasheva A, Fu X, Wang X, Joshi P, Lee V, Dura B, Viero G, Iwasaki A, Fan R, Xiao A, Flavell RA, Li HB, Tebaldi T, Halene S. m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development. Immunity 2020, 52: 1007-1021.e8. PMID: 32497523, PMCID: PMC7408742, DOI: 10.1016/j.immuni.2020.05.003.Peer-Reviewed Original ResearchConceptsDouble-stranded RNADeleterious innate immune responseMammalian hematopoietic developmentEndogenous double-stranded RNAHematopoietic developmentInnate immune responseAbundant RNA modificationMurine fetal liverPattern recognition receptor pathwaysImmune responseProtein codingDsRNA formationRNA modificationsWriter METTL3Hematopoietic defectsPerinatal lethalityNative stateConditional deletionAberrant innate immune responsesLoss of METTL3Hematopoietic failureReceptor pathwayAberrant immune responsePrevents formationFetal liverA highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies
Song Y, Rongvaux A, Taylor A, Jiang T, Tebaldi T, Balasubramanian K, Bagale A, Terzi YK, Gbyli R, Wang X, Fu X, Gao Y, Zhao J, Podoltsev N, Xu M, Neparidze N, Wong E, Torres R, Bruscia EM, Kluger Y, Manz MG, Flavell RA, Halene S. A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies. Nature Communications 2019, 10: 366. PMID: 30664659, PMCID: PMC6341122, DOI: 10.1038/s41467-018-08166-x.Peer-Reviewed Original ResearchConceptsPatient-derived xenograftsMyelodysplastic syndromeXenotransplantation modelDysplastic morphologyImmunodeficient murine hostsPre-clinical studiesMDS stem cellsMDS subtypesComprehensive preclinical studiesPreclinical studiesTherapeutic efficacyMurine hostSerial transplantationDrug mechanismsMDS researchStem cell propagationStem cellsDifferentiation potentialHematopoietic stem cell nicheGenetic complexityNovel avenuesStem cell nicheCell propagationDisease representationsImmunodeficient
2020
Humanized mice as preclinical models for myeloid malignancies
Gbyli R, Song Y, Halene S. Humanized mice as preclinical models for myeloid malignancies. Biochemical Pharmacology 2020, 174: 113794. PMID: 31926939, DOI: 10.1016/j.bcp.2020.113794.Books
2019
Functional Analysis of Human Hematopoietic Stem Cells In Vivo in Humanized Mice
Song Y, Gbyli R, Fu X, Halene S. Functional Analysis of Human Hematopoietic Stem Cells In Vivo in Humanized Mice. Methods In Molecular Biology 2019, 2097: 273-289. PMID: 31776933, DOI: 10.1007/978-1-0716-0203-4_18.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAnimalsAnimals, NewbornAntigens, CD34Cell LineageCell SeparationHematopoietic Stem CellsHumansMiceTransplantation, HeterologousConceptsHematopoietic stem cellsHematopoietic stem cell functionFunctional hematopoietic stem cellsStem cell functionStem cellsCell-intrinsic functionHuman hematopoietic stem cellsOrganismal contextFunctional analysisCell functionIntrinsic functionCell sourceCellular productsChimeric miceStem cell therapyCellsReprogrammingMouse modelMajor advancesCell therapyMiceVivoFunction
2016
Single cell transcriptomics reveals unanticipated features of early hematopoietic precursors
Yang J, Tanaka Y, Seay M, Li Z, Jin J, Garmire LX, Zhu X, Taylor A, Li W, Euskirchen G, Halene S, Kluger Y, Snyder MP, Park IH, Pan X, Weissman SM. Single cell transcriptomics reveals unanticipated features of early hematopoietic precursors. Nucleic Acids Research 2016, 45: 1281-1296. PMID: 28003475, PMCID: PMC5388401, DOI: 10.1093/nar/gkw1214.Peer-Reviewed Original ResearchConceptsHematopoietic stem cellsPrecursor cellsInduction of anemiaInterferon response genesG2/M phaseEarly precursor cellsHomeostatic cellsStages of differentiationTranscription factorsSurface markersCell cycle progressionLong-term hematopoietic stem cellsSpecific augmentationAnemic miceMarked increaseEarly hematopoietic precursorsHematopoietic precursorsStem cellsCycle progressionM phaseSingle-cell transcriptomicsCellsCell differentiationHematopoietic stressLineage-specific transcription factorsPeripheral blood CD34+ cells efficiently engraft human cytokine knock-in mice
Saito Y, Ellegast JM, Rafiei A, Song Y, Kull D, Heikenwalder M, Rongvaux A, Halene S, Flavell RA, Manz MG. Peripheral blood CD34+ cells efficiently engraft human cytokine knock-in mice. Blood 2016, 128: 1829-1833. PMID: 27543436, PMCID: PMC5054696, DOI: 10.1182/blood-2015-10-676452.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornAntigens, CD34CytokinesGene Knock-In TechniquesHematopoietic Stem Cell TransplantationHematopoietic Stem CellsHumansLymphoid TissueMice, TransgenicConceptsPeripheral blood CD34Higher engraftment levelsColony-stimulating factorBone marrowEngraftment levelsHuman hemato-lymphoid systemBlood CD34Granulocyte-macrophage colony-stimulating factorAdult recipient miceNonobese diabetic/Macrophage colony-stimulating factorSignal regulatory protein αCord blood-derived CD34Blood-derived CD34Regulatory protein αMISTRG miceAdult recipientsRecipient miceDiabetic/T cellsNonhematopoietic organsMyeloid cellsImmune systemCD34MiceCooperative Activity of GABP with PU.1 or C/EBPε Regulates Lamin B Receptor Gene Expression, Implicating Their Roles in Granulocyte Nuclear Maturation
Malu K, Garhwal R, Pelletier MG, Gotur D, Halene S, Zwerger M, Yang ZF, Rosmarin AG, Gaines P. Cooperative Activity of GABP with PU.1 or C/EBPε Regulates Lamin B Receptor Gene Expression, Implicating Their Roles in Granulocyte Nuclear Maturation. The Journal Of Immunology 2016, 197: 910-922. PMID: 27342846, PMCID: PMC5022553, DOI: 10.4049/jimmunol.1402285.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCCAAT-Enhancer-Binding ProteinsCell DifferentiationCell NucleusChromatin ImmunoprecipitationElectrophoretic Mobility Shift AssayGA-Binding Protein Transcription FactorGene Expression RegulationGranulocytesHEK293 CellsHematopoietic Stem CellsHumansImmunoblottingMiceMice, Inbred C57BLMutagenesis, Site-DirectedProto-Oncogene ProteinsReal-Time Polymerase Chain ReactionReceptors, Cytoplasmic and NuclearSignal TransductionTrans-ActivatorsConceptsLamin B receptorTranscription factorsGene expressionInner nuclear membrane proteinNuclear membrane proteinsFamily transcription factorsNuclear envelope proteinsETS transcription factorsExpression of genesRole of ETSTranscriptional regulatorsTranscriptional activationCombinatorial actionMembrane proteinsLBR geneEts siteEarly myeloid progenitorsCCAAT enhancerGABPSuch cooperative interactionsNeutrophil differentiationGenesMyeloid progenitorsReceptor gene expressionPromoter
2009
C/EBPε directs granulocytic-vs-monocytic lineage determination and confers chemotactic function via Hlx
Halene S, Gaines P, Sun H, Zibello T, Lin S, Khanna-Gupta A, Williams SC, Perkins A, Krause D, Berliner N. C/EBPε directs granulocytic-vs-monocytic lineage determination and confers chemotactic function via Hlx. Experimental Hematology 2009, 38: 90-103.e4. PMID: 19925846, PMCID: PMC2827304, DOI: 10.1016/j.exphem.2009.11.004.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBone Marrow CellsCCAAT-Enhancer-Binding ProteinsCell DifferentiationCell LineChemotaxis, LeukocyteGene ExpressionGranulocyte-Macrophage Colony-Stimulating FactorGranulocytesHematopoietic Stem CellsHomeodomain ProteinsMiceMice, KnockoutMonocytesMyelopoiesisNeutrophilsReceptors, ChemokineTranscription FactorsTransduction, GeneticConceptsKO cellsNew regulatory functionCommon myeloid progenitorsNeutrophil-specific granule deficiencyProgenitor cell lineCell linesRestoration of expressionDifferentiated cell linesSpecific granule deficiencyLineage-specific cell surface antigensLineage decisionsLineage determinationEpsilon geneCCAAT enhancerDeficiency phenotypeRegulatory functionsChemotaxis defectIntermediate cell typeKO bone marrowPerformed expressionNeutrophil differentiationCell typesFunctional studiesNeutrophil maturationMyeloid progenitors
2000
Gene Therapy Using Hematopoietic Stem Cells: Sisyphus Approaches the Crest
Halene S, Kohn D. Gene Therapy Using Hematopoietic Stem Cells: Sisyphus Approaches the Crest. Human Gene Therapy 2000, 11: 1259-1267. PMID: 10890736, DOI: 10.1089/10430340050032366.Commentaries, Editorials and Letters
1999
Improved Expression in Hematopoietic and Lymphoid Cells in Mice After Transplantation of Bone Marrow Transduced With a Modified Retroviral Vector
Halene S, Wang L, Cooper R, Bockstoce D, Robbins P, Kohn D. Improved Expression in Hematopoietic and Lymphoid Cells in Mice After Transplantation of Bone Marrow Transduced With a Modified Retroviral Vector. Blood 1999, 94: 3349-3357. PMID: 10552944, PMCID: PMC9071851, DOI: 10.1182/blood.v94.10.3349.422k05_3349_3357.Peer-Reviewed Original ResearchMeSH Keywords3T3 CellsAnimalsBone Marrow TransplantationFemaleGene DosageGene ExpressionGene Transfer TechniquesGenetic TherapyGenetic VectorsGreen Fluorescent ProteinsHematopoietic Stem CellsLeukemia Virus, MurineLuminescent ProteinsLymphocytesMaleMiceMice, Inbred C57BLPolymerase Chain ReactionRetroviridaeTime FactorsTransduction, GeneticConceptsEnhanced green fluorescent proteinHematopoietic cellsMoMuLV LTRMammalian hematopoietic cellsMurine embryonic stem cellsStem cellsEmbryonic stem cellsRetroviral vectorsGreen fluorescent proteinMoloney murine leukemia virusMouse bone marrow transplant modelReliable gene expressionHematopoietic stem cellsStable gene transferMurine leukemia virusGene expressionMND vectorTransduction efficiencyFluorescent proteinCopy numberGene transferIndividual cellsAmount of proteinVector copy numberBone marrow transplant model
1998
Consistent, persistent expression from modified retroviral vectors in murine hematopoietic stem cells
Robbins P, Skelton D, Yu X, Halene S, Leonard E, Kohn D. Consistent, persistent expression from modified retroviral vectors in murine hematopoietic stem cells. Proceedings Of The National Academy Of Sciences Of The United States Of America 1998, 95: 10182-10187. PMID: 9707621, PMCID: PMC21482, DOI: 10.1073/pnas.95.17.10182.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceBone Marrow TransplantationColony-Forming Units AssayDNA MethylationDNA PrimersDNA, RecombinantFemaleFounder EffectGene ExpressionGene Transfer TechniquesGenetic VectorsHematopoietic Stem CellsMaleMiceMice, Inbred C57BLMoloney murine leukemia virusRepetitive Sequences, Nucleic AcidRetroviridaeTransduction, GeneticTransplantation, IsogeneicVirus Integration