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-KGHigh-plex protein and whole transcriptome co-mapping at cellular resolution with spatial CITE-seq
Liu Y, DiStasio M, Su G, Asashima H, Enninful A, Qin X, Deng Y, Nam J, Gao F, Bordignon P, Cassano M, Tomayko M, Xu M, Halene S, Craft J, Hafler D, Fan R. High-plex protein and whole transcriptome co-mapping at cellular resolution with spatial CITE-seq. Nature Biotechnology 2023, 41: 1405-1409. PMID: 36823353, PMCID: PMC10567548, DOI: 10.1038/s41587-023-01676-0.Peer-Reviewed Original ResearchMicrofluidic Immuno‐Serolomic Assay Reveals Systems Level Association with COVID‐19 Pathology and Vaccine Protection
Kim D, Biancon G, Bai Z, VanOudenhove J, Liu Y, Kothari S, Gowda L, Kwan J, Buitrago‐Pocasangre N, Lele N, Asashima H, Racke M, Wilson J, Givens T, Tomayko M, Schulz W, Longbrake E, Hafler D, Halene S, Fan R. Microfluidic Immuno‐Serolomic Assay Reveals Systems Level Association with COVID‐19 Pathology and Vaccine Protection. Small Methods 2023, 7: e2300594. PMID: 37312418, PMCID: PMC10592458, DOI: 10.1002/smtd.202300594.Peer-Reviewed Original ResearchConceptsB cell depletion therapyAcute COVID infectionAnti-spike IgGHigh-risk patientsCoronavirus disease-19COVID-19 pathologyDepletion therapyVaccine protectionAntibody responseCOVID infectionHematologic malignanciesImmune protectionDisease-19Healthy donorsMultiple time pointsSerology assaysBlood samplesSoluble markersB cellsImmunization strategiesPatientsFunctional deficiencySerological analysisTime pointsClonotype diversityPrecision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies
Biancon G, Joshi P, Zimmer JT, Hunck T, Gao Y, Lessard MD, Courchaine E, Barentine AES, Machyna M, Botti V, Qin A, Gbyli R, Patel A, Song Y, Kiefer L, Viero G, Neuenkirchen N, Lin H, Bewersdorf J, Simon MD, Neugebauer KM, Tebaldi T, Halene S. Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies. Molecular Cell 2022, 82: 1107-1122.e7. PMID: 35303483, PMCID: PMC8988922, DOI: 10.1016/j.molcel.2022.02.025.Peer-Reviewed Original ResearchDeconvolution of in vivo protein-RNA contacts using fractionated eCLIP-seq
Biancon G, Busarello E, Joshi P, Lesch B, Halene S, Tebaldi T. Deconvolution of in vivo protein-RNA contacts using fractionated eCLIP-seq. STAR Protocols 2022, 3: 101823. PMID: 36595959, PMCID: PMC9676202, DOI: 10.1016/j.xpro.2022.101823.Peer-Reviewed Original ResearchConceptsProtein-RNA interactionsIndividual RNA-binding proteinsTranscriptome-wide analysisThousands of RNAsProtein-RNA contactsRNA-binding proteinSingle nucleotide levelComputational analysis pipelineRNA processingMulticomponent complexesRNA immunoprecipitationRead countsComplete detailsAnalysis pipelineAdditional levelProteinImmunoprecipitationRNAInteractionComplexesIs it the time to integrate novel sequencing technologies into clinical practice?
VanOudenhove J, Halene S, Mendez L. Is it the time to integrate novel sequencing technologies into clinical practice? Current Opinion In Hematology 2022, 30: 70-77. PMID: 36602939, DOI: 10.1097/moh.0000000000000754.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsNovel sequencing technologiesSequencing technologiesUnprecedented biological insightsNext-generation sequencing techniquesDNA sequencing technologiesHigh-throughput NGSRare cell populationsBiological insightsMultiomics approachSequencing techniquesGenotype-phenotype correlationClonal diversityCellular resolutionMechanistic insightsCell populationsPhenotype correlationMyeloid diseasesClonesClonal hierarchyClonal haematopoiesisResidual clonesInsightsSeqDiversityImproved captureIn vivo anti-tumor effect of PARP inhibition in IDH1/2 mutant MDS/AML resistant to targeted inhibitors of mutant IDH1/2
Gbyli R, Song Y, Liu W, Gao Y, Biancon G, Chandhok NS, Wang X, Fu X, Patel A, Sundaram R, Tebaldi T, Mamillapalli P, Zeidan AM, Flavell RA, Prebet T, Bindra RS, Halene S. In vivo anti-tumor effect of PARP inhibition in IDH1/2 mutant MDS/AML resistant to targeted inhibitors of mutant IDH1/2. Leukemia 2022, 36: 1313-1323. PMID: 35273342, PMCID: PMC9103411, DOI: 10.1038/s41375-022-01536-x.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaMyelodysplastic syndromeMDS/acute myeloid leukemiaRefractory acute myeloid leukemiaPARP inhibitionVivo anti-tumor effectsAlternate therapeutic optionsSubset of AMLAnti-tumor effectsPre-clinical studiesRibose polymerase inhibitorsSerial transplantation assaysHomologous recombination defectsTherapeutic optionsTreatment optionsOverall engraftmentHigh relapseIDH inhibitionMyeloid leukemiaIsocitrate dehydrogenase 1Small molecule inhibitorsCell frequencyXeno-graftsIDH1/2 mutationsMalignant transformationCombined 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 representationsImmunodeficientHow do messenger RNA splicing alterations drive myelodysplasia?
Joshi P, Halene S, Abdel-Wahab O. How do messenger RNA splicing alterations drive myelodysplasia? Blood 2017, 129: 2465-2470. PMID: 28348147, PMCID: PMC5418633, DOI: 10.1182/blood-2017-02-692715.Commentaries, Editorials and Letters
2024
Ezrin drives adaptation of monocytes to the inflamed lung microenvironment
Gudneppanavar R, Di Pietro C, H Öz H, Zhang P, Cheng E, Huang P, Tebaldi T, Biancon G, Halene S, Hoppe A, Kim C, Gonzalez A, Krause D, Egan M, Gupta N, Murray T, Bruscia E. Ezrin drives adaptation of monocytes to the inflamed lung microenvironment. Cell Death & Disease 2024, 15: 864. PMID: 39613751, PMCID: PMC11607083, DOI: 10.1038/s41419-024-07255-8.Peer-Reviewed Original ResearchConceptsActivation of focal adhesion kinaseExtracellular matrixActin-binding proteinsFocal adhesion kinaseLung extracellular matrixKnock-out mouse modelProtein kinase signalingCortical cytoskeletonLoss of ezrinKinase signalingPlasma membraneCell migrationSignaling pathwayEzrinResponse to lipopolysaccharideTissue-resident macrophagesMouse modelLipopolysaccharideCytoskeletonEzrin expressionLung microenvironmentKinaseMonocyte recruitmentProteinAktClonal hematopoiesis of indeterminate potential is associated with increased risk of immune checkpoint inhibitor myocarditis in a prospective study of a cardio-oncology cohort
Jaber Chehayeb R, Singh J, Matute-Martinez C, Chen N, Guajardo A, Lin D, Jayakrishnan R, Christofides A, Leveille E, Im Y, Biancon G, VanOudenhove J, Ibrahim E, Ardasheva A, Jha A, Hwa J, Halene S, Kwan J. Clonal hematopoiesis of indeterminate potential is associated with increased risk of immune checkpoint inhibitor myocarditis in a prospective study of a cardio-oncology cohort. Cardio-Oncology 2024, 10: 84. PMID: 39587635, PMCID: PMC11590368, DOI: 10.1186/s40959-024-00289-z.Peer-Reviewed Original ResearchImmune checkpoint inhibitor myocarditisImmune checkpoint inhibitorsImmune checkpoint inhibitor useICI-myocarditisIndeterminate potentialProspective studyImmune checkpoint inhibitor therapyCancer therapyClonal hematopoiesis of indeterminate potentialCancer treated with immunotherapyIncreased T cell activationObstructive coronary artery diseaseMultivariate competing risk analysisCardiotoxic cancer therapyRisks Cox regressionAssociated with increased riskIncreased all-cause mortalityPatient co-morbiditiesRisk of cardiomyopathyT cell activationCompeting risk analysisCoronary artery calcificationCoronary artery diseaseAll-cause mortalityHeart failure patientsGPR68 supports AML cells through the calcium/calcineurin pro-survival pathway and confers chemoresistance by mediating glucose metabolic symbiosis
He X, Hawkins C, Lawley L, Phan T, Park I, Joven N, Zhang J, Wunderlich M, Mizukawa B, Pei S, Patel A, VanOudenhove J, Halene S, Fang J. GPR68 supports AML cells through the calcium/calcineurin pro-survival pathway and confers chemoresistance by mediating glucose metabolic symbiosis. Biochimica Et Biophysica Acta (BBA) - Molecular Basis Of Disease 2024, 167565. PMID: 39522891, DOI: 10.1016/j.bbadis.2024.167565.Peer-Reviewed Original ResearchAcute myeloid leukemiaAcute myeloid leukemia cellsPro-survival pathwaysInhibiting isocitrate dehydrogenaseMetabolic symbiosisMyelodysplastic syndromeHematopoietic malignanciesExtracellular acidosisAssociated with inferior clinical outcomesCellular respirationFirst-line chemotherapeutic agentAcute myeloid leukemia patientsInferior clinical outcomesAerobic glycolysisCell survival in vitroEngraftment in vivoDecreased Ca<sup>2+</sup> levelDecreased aerobic glycolysisSurvival in vitroGlucose metabolic pathwaysG protein-coupled receptor 68Impacts chemosensitivityIn vitro observationsTumoricidal effectMyeloid leukemiaSplicing the Difference: Harnessing the Complexity of the Transcriptome in Hematopoiesis
Maul-Newby H, Halene S. Splicing the Difference: Harnessing the Complexity of the Transcriptome in Hematopoiesis. Experimental Hematology 2024, 140: 104655. PMID: 39393608, DOI: 10.1016/j.exphem.2024.104655.Peer-Reviewed Original ResearchAlternative splicingAlternative splicing eventsStem cell maintenanceSplicing factor mutationsHematopoietic stem cell maintenanceExpression of beta-globinField of stem cell researchSplicing eventsSplicing factorsFunctional blood cellsAberrant splicingStudy of hematopoiesisComplex regulationCell maintenanceSplicingCellular differentiationBeta-globinMyelodysplastic syndromeMyeloid malignanciesHematologic malignanciesStem cell researchCell sortingMutationsTranscriptomeAberrant expressionContemporary Approach to the Diagnosis and Classification of Myelodysplastic Neoplasms/Syndromes—Recommendations From the International Consortium for Myelodysplastic Neoplasms/Syndromes (MDS [icMDS])
Aakash F, Gisriel S, Zeidan A, Bennett J, Bejar R, Bewersdorf J, Borate U, Boultwood J, Brunner A, Buckstein R, Carraway H, Churpek J, Daver N, DeZern A, Efficace F, Fenaux P, Figueroa M, Garcia-Manero G, Gore S, Greenberg P, Griffiths E, Halene S, Hourigan C, Kim T, Kim N, Komrokji R, Kutchroo V, List A, Little R, Majeti R, Nazha A, Nimer S, Odenike O, Padron E, Patnaik M, Platzbecker U, Della Porta M, Roboz G, Sallman D, Santini V, Sanz G, Savona M, Sekeres M, Stahl M, Starczynowski D, Steensma D, Taylor J, Abdel-Wahab O, Wei A, Xie Z, Xu M, Hasserjian R, Loghavi S. Contemporary Approach to the Diagnosis and Classification of Myelodysplastic Neoplasms/Syndromes—Recommendations From the International Consortium for Myelodysplastic Neoplasms/Syndromes (MDS [icMDS]). Modern Pathology 2024, 37: 100615. PMID: 39322118, DOI: 10.1016/j.modpat.2024.100615.Peer-Reviewed Original ResearchAplastic anemia in association with multiple myeloma: clinical and pathophysiological insights
Muradashvili T, Liu Y, VanOudenhove J, Gu S, Krause D, Montanari F, Carlino M, Mancuso R, Stempel J, Halene S, Zeidan A, Podoltsev N, Neparidze N. Aplastic anemia in association with multiple myeloma: clinical and pathophysiological insights. Leukemia & Lymphoma 2024, ahead-of-print: 1-8. PMID: 39225418, DOI: 10.1080/10428194.2024.2393260.Peer-Reviewed Original ResearchAplastic anemiaMultiple myelomaImmunosuppressive therapyTransfusion requirementsProgenitor cellsPlasma cell-directed therapyT-cell destructionCell-directed therapiesInhibition of erythroid colony formationErythroid colony formationLevels of IL8Severe AAImmune cytopeniasPartial responseMM patientsHematopoietic stemSerum testsPartial improvementPathophysiological insightsPatientsImmune systemPlatelet apoptosisCytopeniasColony formationMyelomaThe 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