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 ResearchConceptsAlkB 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 hepatocytesMiceTranscriptome-wide quantification of double-stranded RNAs in live mouse tissues by dsRIP-Seq
Gao Y, Chen S, Halene S, Tebaldi T. Transcriptome-wide quantification of double-stranded RNAs in live mouse tissues by dsRIP-Seq. STAR Protocols 2021, 2: 100366. PMID: 33778776, PMCID: PMC7982789, DOI: 10.1016/j.xpro.2021.100366.Peer-Reviewed Original ResearchConceptsDouble-stranded RNALive mouse tissuesDeleterious innate immune responseInnate immune responseEndogenous double-stranded RNAMouse tissuesMultiple regulatory functionsRecognition of RNADownstream computational analysisImmune responseRNA editingActivate innate immune responsesRegulatory functionsComplete detailsRNAImmunoprecipitationTissue isolationComplete protocolGao etComputational analysisSequencingTissueEditingm6A 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 liverHigh-Spatial-Resolution Multi-Omics Sequencing via Deterministic Barcoding in Tissue
Liu Y, Yang M, Deng Y, Su G, Enninful A, Guo CC, Tebaldi T, Zhang D, Kim D, Bai Z, Norris E, Pan A, Li J, Xiao Y, Halene S, Fan R. High-Spatial-Resolution Multi-Omics Sequencing via Deterministic Barcoding in Tissue. Cell 2020, 183: 1665-1681.e18. PMID: 33188776, PMCID: PMC7736559, DOI: 10.1016/j.cell.2020.10.026.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutomationBrainCluster AnalysisDNA Barcoding, TaxonomicDNA, ComplementaryEmbryo, MammalianEyeFemaleGene Expression Regulation, DevelopmentalGenomicsHuman Umbilical Vein Endothelial CellsHumansMice, Inbred C57BLMicrofluidicsOrgan SpecificityReproducibility of ResultsRNA, MessengerSingle-Cell AnalysisTranscriptomeConceptsDeterministic barcodingNext-generation sequencingSingle-cell transcriptomesGene expression profilesMajor tissue typesDBiT-seqDNA barcodesDevelopmental biologyExpression profilesEarly organogenesisCancer biologyCell typesBarcodingTissue typesSequencingBarcodesBiologyRapid identificationSets of barcodesTranscriptomeParallel microfluidic channelsOrganogenesisEmbryosProteinTissue pixelsA 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
2024
The human CD47 checkpoint is targeted by an immunosuppressive Aedes aegypti salivary factor to enhance arboviral skin infectivity
Marin-Lopez A, Huck J, Esterly A, Azcutia V, Rosen C, Garcia-Milian R, Sefik E, Vidal-Pedrola G, Raduwan H, Chen T, Arora G, Halene S, Shaw A, Palm N, Flavell R, Parkos C, Thangamani S, Ring A, Fikrig E. The human CD47 checkpoint is targeted by an immunosuppressive Aedes aegypti salivary factor to enhance arboviral skin infectivity. Science Immunology 2024, 9: eadk9872. PMID: 39121194, DOI: 10.1126/sciimmunol.adk9872.Peer-Reviewed Original ResearchConceptsSuppress antiviral responsesArthropod proteinsPathogen replicationAntiviral responseProtein AVertebrate hostsMosquito salivary proteinsUp-regulatedBlood feedingHuman macrophagesPleomorphic effectsSkin infectionsZika virus disseminationInhibit proinflammatory responsesSalivary proteinsProteinNatural ligandWhite blood cellsHuman skin explantsProinflammatory responseMosquito salivaVirus disseminationHuman CD47Salivary factorsArbovirus infection
2023
Current landscape of translational and clinical research in myelodysplastic syndromes/neoplasms (MDS): Proceedings from the 1st International Workshop on MDS (iwMDS) Of the International Consortium for MDS (icMDS)
Bewersdorf J, Xie Z, Bejar R, Borate U, Boultwood J, Brunner A, Buckstein R, Carraway H, Churpek J, Daver N, Porta M, DeZern A, Fenaux P, Figueroa M, Gore S, Griffiths E, Halene S, Hasserjian R, Hourigan C, Kim T, Komrokji R, Kuchroo V, List A, Loghavi S, Majeti R, Odenike O, Patnaik M, Platzbecker U, Roboz G, Sallman D, Santini V, Sanz G, Sekeres M, Stahl M, Starczynowski D, Steensma D, Taylor J, Abdel-Wahab O, Xu M, Savona M, Wei A, Zeidan A. Current landscape of translational and clinical research in myelodysplastic syndromes/neoplasms (MDS): Proceedings from the 1st International Workshop on MDS (iwMDS) Of the International Consortium for MDS (icMDS). Blood Reviews 2023, 60: 101072. PMID: 36934059, DOI: 10.1016/j.blre.2023.101072.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsImmune checkpoint inhibitorsSpecific molecular alterationsNovel animal modelInnate immune systemCheckpoint inhibitorsImmune dysregulationMDS patientsClinical trialsNovel therapiesTherapeutic strategiesAnimal modelsGermline predispositionImmune systemMolecular alterationsClinical researchInternational ConsortiumNeoplasmsClinical workGenetic landscapeInternational WorkshopPatientsCurrent landscapePathogenesisTherapyDisease
2022
Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis
Öz H, Cheng E, Di Pietro C, Tebaldi T, Biancon G, Zeiss C, Zhang P, Huang P, Esquibies S, Britto C, Schupp J, Murray T, Halene S, Krause D, Egan M, Bruscia E. Recruited monocytes/macrophages drive pulmonary neutrophilic inflammation and irreversible lung tissue remodeling in cystic fibrosis. Cell Reports 2022, 41: 111797. PMID: 36516754, PMCID: PMC9833830, DOI: 10.1016/j.celrep.2022.111797.Peer-Reviewed Original ResearchConceptsC motif chemokine receptor 2Monocytes/macrophagesLung tissue damageCystic fibrosisTissue damageCF lungPulmonary neutrophilic inflammationPro-inflammatory environmentChemokine receptor 2CF lung diseaseNumber of monocytesSpecific therapeutic agentsGrowth factor βCF transmembrane conductance regulatorLung hyperinflammationLung neutrophiliaNeutrophilic inflammationNeutrophil inflammationInflammation contributesLung damageNeutrophil recruitmentLung diseaseLung tissueReceptor 2Therapeutic targetHuman neutrophil development and functionality are enabled in a humanized mouse model
Zheng Y, Sefik E, Astle J, Karatepe K, Öz HH, Solis AG, Jackson R, Luo HR, Bruscia EM, Halene S, Shan L, Flavell RA. Human neutrophil development and functionality are enabled in a humanized mouse model. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2121077119. PMID: 36269862, PMCID: PMC9618085, DOI: 10.1073/pnas.2121077119.Peer-Reviewed Original ResearchConceptsHumanized mouse modelMouse modelHuman immune systemHuman neutrophilsImmune systemFunctional human immune systemGranulocyte colony-stimulating factorUnique mouse modelColony-stimulating factorHuman G-CSFMISTRG miceG-CSF receptor geneBacterial burdenInfectious challengeG-CSFNeutrophilsMiceNeutrophil developmentReceptor geneDiseaseSelective inhibition of MCL1 overcomes venetoclax resistance in a murine model of myelodysplastic syndromes
Fischer MA, Song Y, Arrate MP, Gbyli R, Villaume MT, Smith BN, Childress MA, Stricker TP, Halene S, Savona MR. Selective inhibition of MCL1 overcomes venetoclax resistance in a murine model of myelodysplastic syndromes. Haematologica 2022, 108: 522-531. PMID: 35979721, PMCID: PMC9890032, DOI: 10.3324/haematol.2022.280631.Peer-Reviewed Original ResearchConceptsB-cell lymphoma 2Acute myeloid leukemiaMyeloid cell leukemia-1Myelodysplastic syndromeMDS subtypesHigh-risk myelodysplastic syndromeMCL1 inhibitionRisk myelodysplastic syndromesAnti-apoptotic protein B-cell lymphoma 2Protein B-cell lymphoma 2Effective clinical therapySelective inhibitorMDS patient samplesAttractive therapeutic opportunityBcl-xLExcess blastsOlder patientsClinical trialsMyeloid leukemiaMurine modelImpressive responseSignificant injuryAnti-apoptotic protein Bcl-xLLeukemia survivalLymphoma 2Spatial profiling of chromatin accessibility in mouse and human tissues
Deng Y, Bartosovic M, Ma S, Zhang D, Kukanja P, Xiao Y, Su G, Liu Y, Qin X, Rosoklija GB, Dwork AJ, Mann JJ, Xu ML, Halene S, Craft JE, Leong KW, Boldrini M, Castelo-Branco G, Fan R. Spatial profiling of chromatin accessibility in mouse and human tissues. Nature 2022, 609: 375-383. PMID: 35978191, PMCID: PMC9452302, DOI: 10.1038/s41586-022-05094-1.Peer-Reviewed Original ResearchConceptsChromatin accessibilityATAC-seqSpecific epigenetic landscapesChromatin accessibility profilingCell fate decisionsEpigenetic informationEpigenetic landscapeGenome scaleFate decisionsAccessible genomeCell identityEpigenetic underpinningsNext-generation sequencingGene regulatorsCell statesMouse embryosSpatial biologySpatial transcriptomicsCell typesCellular levelImmune cell typesDistinct organizationHuman tissuesProfilingSpatial profilingInflammasome activation in infected macrophages drives COVID-19 pathology
Sefik E, Qu R, Junqueira C, Kaffe E, Mirza H, Zhao J, Brewer JR, Han A, Steach HR, Israelow B, Blackburn HN, Velazquez SE, Chen YG, Halene S, Iwasaki A, Meffre E, Nussenzweig M, Lieberman J, Wilen CB, Kluger Y, Flavell RA. Inflammasome activation in infected macrophages drives COVID-19 pathology. Nature 2022, 606: 585-593. PMID: 35483404, PMCID: PMC9288243, DOI: 10.1038/s41586-022-04802-1.Peer-Reviewed Original ResearchConceptsInflammasome activationLung inflammationInflammatory responseInfected macrophagesSARS-CoV-2 infectionHuman macrophagesChronic lung pathologyPersistent lung inflammationSevere COVID-19Immune inflammatory responseInflammatory cytokine productionHumanized mouse modelNLRP3 inflammasome pathwayCOVID-19 pathologyCOVID-19SARS-CoV-2Productive viral cycleHyperinflammatory stateChronic stageIL-18Cytokine productionInflammatory cytokinesLung pathologyInflammasome pathwayInterleukin-1
2021
A humanized mouse model of chronic COVID-19
Sefik E, Israelow B, Mirza H, Zhao J, Qu R, Kaffe E, Song E, Halene S, Meffre E, Kluger Y, Nussenzweig M, Wilen CB, Iwasaki A, Flavell RA. A humanized mouse model of chronic COVID-19. Nature Biotechnology 2021, 40: 906-920. PMID: 34921308, PMCID: PMC9203605, DOI: 10.1038/s41587-021-01155-4.Peer-Reviewed Original ResearchConceptsChronic COVID-19Humanized mouse modelImmune responseMouse modelAcute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infectionSyndrome coronavirus 2 infectionCOVID-19Adaptive human immune responsesInterferon-stimulated gene signaturePersistent viral RNACoronavirus 2 infectionPatient-derived antibodiesT-cell lymphopeniaHuman immune responseHyperactive immune responseCoronavirus disease 2019Inflammatory macrophage responseImmunological injuryLung pathologyCell lymphopeniaDisease 2019Severe diseaseRodent modelsInflammatory macrophages
2020
Cyclosporine enhances the sensitivity to lenalidomide in MDS/AML in vitro
He X, Dou A, Feng S, Roman-Rivera A, Hawkins C, Lawley L, Zhang J, Wunderlich M, Mizukawa B, Halene S, Patel A, Fang J. Cyclosporine enhances the sensitivity to lenalidomide in MDS/AML in vitro. Experimental Hematology 2020, 86: 21-27.e2. PMID: 32437909, PMCID: PMC7335335, DOI: 10.1016/j.exphem.2020.05.001.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell Line, TumorCyclosporineDNA-Binding ProteinsDrug Resistance, NeoplasmGene Expression Regulation, LeukemicHumansIkaros Transcription FactorLenalidomideLeukemia, Myeloid, AcuteMiceMice, Inbred NODMuscle ProteinsMyelodysplastic SyndromesNeoplasm ProteinsUp-RegulationXenograft Model Antitumor AssaysConceptsAcute myeloid leukemiaMDS/acute myeloid leukemiaMyelodysplastic syndromeT cell activationAML patient-derived xenograft modelsG protein-coupled receptor 68MDS/AML cellsPatient-derived xenograft modelsMDS/AML cell linesDegradation of IKZF1AML cell linesCell linesActivity of CaNBone marrow cellsMDS patientsPrimary bone marrow cellsHematologic malignanciesMyeloid leukemiaAML cellsLenalidomideXenograft modelDrug AdministrationSuppressive effectProsurvival pathwaysMarrow cellsDesign of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia Activity
Li X, Jiang Y, Peterson YK, Xu T, Himes RA, Luo X, Yin G, Inks ES, Dolloff N, Halene S, Chan SSL, Chou CJ. Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia Activity. Journal Of Medicinal Chemistry 2020, 63: 5501-5525. PMID: 32321249, PMCID: PMC7684764, DOI: 10.1021/acs.jmedchem.0c00442.Peer-Reviewed Original ResearchHumanized 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
The minimal that kills: Why defining and targeting measurable residual disease is the “Sine Qua Non” for further progress in management of acute myeloid leukemia
Bewersdorf JP, Shallis RM, Boddu PC, Wood B, Radich J, Halene S, Zeidan AM. The minimal that kills: Why defining and targeting measurable residual disease is the “Sine Qua Non” for further progress in management of acute myeloid leukemia. Blood Reviews 2019, 43: 100650. PMID: 31883804, DOI: 10.1016/j.blre.2019.100650.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsAcute myeloid leukemiaMyeloid leukemiaHard clinical outcomesClinical trial evidenceMeasurable residual diseaseResidual leukemic cellsRisk of relapseApprovable endpointsMRD statusDeep remissionMorphologic remissionMRD assessmentOverall survivalMRD levelsClinical outcomesDisease relapseInitial treatmentResidual diseaseTrial evidenceClinical trialsTreatment decisionsSurrogate endpointsBone marrowPreemptive interventionLeukemic cellsFunctional 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 StatementsConceptsHematopoietic 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 therapyMiceVivoFunctionLAM-003, a new drug for treatment of tyrosine kinase inhibitor–resistant FLT3-ITD–positive AML
Beeharry N, Landrette S, Gayle S, Hernandez M, Grotzke JE, Young PR, Beckett P, Zhang X, Carter BZ, Andreeff M, Halene S, Xu T, Rothberg J, Lichenstein H. LAM-003, a new drug for treatment of tyrosine kinase inhibitor–resistant FLT3-ITD–positive AML. Blood Advances 2019, 3: 3661-3673. PMID: 31751472, PMCID: PMC6880894, DOI: 10.1182/bloodadvances.2019001068.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Line, TumorDisease Models, AnimalDose-Response Relationship, DrugDrug Resistance, NeoplasmDrug SynergismEpigenesis, GeneticFms-Like Tyrosine Kinase 3Gene DuplicationGene Expression Regulation, LeukemicHumansLeukemia, Myeloid, AcuteMiceMutationProtein Kinase InhibitorsConceptsAcute myeloid leukemiaAML cell linesFLT3 inhibitorsFLT3-ITDSingle agentPositive acute myeloid leukemiaFLT3 inhibitor therapyStromal-conditioned mediumInitial clinical responseInternal tandem duplication mutationsFLT3-ITD patientsPoor patient prognosisXenograft mouse modelCell linesFLT3 kinase inhibitorsTandem duplication mutationsDiscovery of synergyWide CRISPR screenClinical responseTyrosine kinase receptorsInhibitor therapyPreclinical findingsBcl-2 inhibitorsMechanisms of resistancePatient prognosis