2022
Multiparameter analysis of timelapse imaging reveals kinetics of megakaryocytic erythroid progenitor clonal expansion and differentiation
Scanlon VM, Thompson EN, Lawton BR, Kochugaeva M, Ta K, Mayday MY, Xavier-Ferrucio J, Kang E, Eskow NM, Lu YC, Kwon N, Laumas A, Cenci M, Lawrence K, Barden K, Larsuel ST, Reed FE, Peña-Carmona G, Ubbelohde A, Lee JP, Boobalan S, Oppong Y, Anderson R, Maynard C, Sahirul K, Lajeune C, Ivathraya V, Addy T, Sanchez P, Holbrook C, Van Ho AT, Duncan JS, Blau HM, Levchenko A, Krause DS. Multiparameter analysis of timelapse imaging reveals kinetics of megakaryocytic erythroid progenitor clonal expansion and differentiation. Scientific Reports 2022, 12: 16218. PMID: 36171423, PMCID: PMC9519589, DOI: 10.1038/s41598-022-19013-x.Peer-Reviewed Original ResearchConceptsMegakaryocytic-erythroid progenitorsFate specificationLineage commitmentUnderstanding of hematopoiesisProgenitor cell biologyPrimary human hematopoietic progenitorsSingle-cell trackingSingle-cell assaysSingle-cell levelHuman hematopoietic progenitorsProgenitor cell dynamicsLineage specificationCell fateColony-forming unit assaysTimelapse imagingSitu fluorescence stainingCell biologyLineage tracingDivision rateCytokine thrombopoietinHematopoietic progenitorsProgenitorsFluorescence stainingCell dynamicsUnit assaysStructure-function analysis of the role of megakaryoblastic leukemia 1 in megakaryocyte polyploidization
Reed F, Eskow N, Min E, Carlino M, Mancuso R, Kwon N, Smith E, Larsuel S, Wang L, Scanlon V, Krause D. Structure-function analysis of the role of megakaryoblastic leukemia 1 in megakaryocyte polyploidization. Haematologica 2022, 107: 2972-2976. PMID: 36453520, PMCID: PMC9713552, DOI: 10.3324/haematol.2021.280499.Peer-Reviewed Original Research
2021
Methylation of dual-specificity phosphatase 4 controls cell differentiation
Su H, Jiang M, Senevirathne C, Aluri S, Zhang T, Guo H, Xavier-Ferrucio J, Jin S, Tran NT, Liu SM, Sun CW, Zhu Y, Zhao Q, Chen Y, Cable L, Shen Y, Liu J, Qu CK, Han X, Klug CA, Bhatia R, Chen Y, Nimer SD, Zheng YG, Iancu-Rubin C, Jin J, Deng H, Krause DS, Xiang J, Verma A, Luo M, Zhao X. Methylation of dual-specificity phosphatase 4 controls cell differentiation. Cell Reports 2021, 36: 109421. PMID: 34320342, PMCID: PMC9110119, DOI: 10.1016/j.celrep.2021.109421.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsArginineCell DifferentiationCell LineChildDual-Specificity PhosphatasesEnzyme StabilityFemaleHEK293 CellsHumansMaleMAP Kinase Signaling SystemMegakaryocytesMethylationMice, Inbred C57BLMiddle AgedMitogen-Activated Protein Kinase PhosphatasesMyelodysplastic SyndromesP38 Mitogen-Activated Protein KinasesPolyubiquitinProtein-Arginine N-MethyltransferasesProteolysisRepressor ProteinsUbiquitinationYoung AdultConceptsDual-specificity phosphataseCell differentiationSingle-cell transcriptional analysisP38 MAPKControls cell differentiationE3 ligase HUWE1Knockdown screeningMK differentiationTranscriptional analysisMegakaryocyte differentiationProtein kinaseP38 axisP38 activationPRMT1Transcriptional signatureContext of thrombocytopeniaMK cellsMechanistic insightsPharmacological inhibitionDifferentiationMethylationMAPKPhosphataseUbiquitinylationActivation
2020
Current understanding of human megakaryocytic-erythroid progenitors and their fate determinants.
Kwon N, Thompson EN, Mayday MY, Scanlon V, Lu YC, Krause DS. Current understanding of human megakaryocytic-erythroid progenitors and their fate determinants. Current Opinion In Hematology 2020, 28: 28-35. PMID: 33186151, PMCID: PMC7737300, DOI: 10.1097/moh.0000000000000625.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineageErythroid CellsHematopoiesisHumansMegakaryocyte-Erythroid Progenitor CellsMegakaryocytesTranscriptomeConceptsMegakaryocyte-erythroid progenitorsFate decisionsCell fate decisionsMegakaryocytic-erythroid progenitorsGene expression patternsProgenitor cell biologyFate determinantsFate determinationCurrent understandingTranscription factorsCell biologyExpression patternsPluripotent progenitorsProgenitorsModel systemExtrinsic factorsBiologyDisease statesFateDevelopment leadEpigeneticsMegakaryocytesUnderstandingDiscoveryIsolation
2019
Low iron promotes megakaryocytic commitment of megakaryocytic-erythroid progenitors in humans and mice
Xavier-Ferrucio J, Scanlon V, Li X, Zhang PX, Lozovatsky L, Ayala-Lopez N, Tebaldi T, Halene S, Cao C, Fleming MD, Finberg KE, Krause DS. Low iron promotes megakaryocytic commitment of megakaryocytic-erythroid progenitors in humans and mice. Blood 2019, 134: 1547-1557. PMID: 31439541, PMCID: PMC6839952, DOI: 10.1182/blood.2019002039.Peer-Reviewed Original ResearchConceptsMK lineage commitmentExtracellular signal-regulated kinase (ERK) pathwaySignal-regulated kinase pathwayMegakaryocytic-erythroid progenitorsBone marrow transplantation assaysSignal transduction analysisIron-deficient conditionsGene expression analysisMegakaryocytic commitmentLineage commitmentTransferrin receptor 2MK lineageTmprss6-/- miceIron sensorExpression analysisKinase pathwayTransduction analysisTransplantation assaysErythroid progenitorsMarrow environmentHematopoietic cellsMessenger RNAPhospho-ERK1/2Systemic iron deficiencyLow ironEpithelial (E)-Cadherin is a Novel Mediator of Platelet Aggregation and Clot Stability
Scanlon VM, Teixeira AM, Tyagi T, Zou S, Zhang PX, Booth CJ, Kowalska MA, Bao J, Hwa J, Hayes V, Marks MS, Poncz M, Krause DS. Epithelial (E)-Cadherin is a Novel Mediator of Platelet Aggregation and Clot Stability. Thrombosis And Haemostasis 2019, 119: 744-757. PMID: 30861547, PMCID: PMC6599679, DOI: 10.1055/s-0039-1679908.Peer-Reviewed Original ResearchConceptsConditional knockout miceKnockout micePlatelet aggregationE-cadherinClot stabilityClot stabilizationSynthase kinase 3β activationAntibody-mediated platelet depletionVivo injury modelsNull plateletsPlatelet productionWild-type miceTail bleeding timeAkt/GSK3βMurine platelet aggregationKnockout mouse modelPlatelet dysfunctionFibrin depositionInjury modelPlatelet depletionPrimary human plateletsBleeding timeMouse modelPlatelet numberE-cadherin antibody
2018
MRTFA augments megakaryocyte maturation by enhancing the SRF regulatory axis
Rahman NT, Schulz VP, Wang L, Gallagher PG, Denisenko O, Gualdrini F, Esnault C, Krause DS. MRTFA augments megakaryocyte maturation by enhancing the SRF regulatory axis. Blood Advances 2018, 2: 2691-2703. PMID: 30337297, PMCID: PMC6199649, DOI: 10.1182/bloodadvances.2018019448.Peer-Reviewed Original ResearchConceptsSerum response factorHEL cellsTarget genesBinding of SRFMegakaryocyte maturationActivity of SRFSRF target genesUpregulated target genesMyocardin family proteinsTernary complex factor familyTransformation-specific proteinsPrimary hematopoietic cellsHuman erythroleukemia cell lineErythroleukemia cell lineCArG sitesPrimary human CD34Genomic sitesGenomic regionsChromatin immunoprecipitationETS factorsTranscription factorsHuman megakaryopoiesisGenomic associationsMRTFAFactor family
2017
SNP in human ARHGEF3 promoter is associated with DNase hypersensitivity, transcript level and platelet function, and Arhgef3 KO mice have increased mean platelet volume
Zou S, Teixeira AM, Kostadima M, Astle WJ, Radhakrishnan A, Simon LM, Truman L, Fang JS, Hwa J, Zhang PX, van der Harst P, Bray PF, Ouwehand WH, Frontini M, Krause DS. SNP in human ARHGEF3 promoter is associated with DNase hypersensitivity, transcript level and platelet function, and Arhgef3 KO mice have increased mean platelet volume. PLOS ONE 2017, 12: e0178095. PMID: 28542600, PMCID: PMC5441597, DOI: 10.1371/journal.pone.0178095.Peer-Reviewed Original ResearchConceptsExpression quantitative lociMK maturationGene expressionRho guanine exchange factorsHuman megakaryocytesGenome-wide association studiesDNase I hypersensitive regionGuanine exchange factorHuman genetic studiesExchange factorReporter mouse modelDNase hypersensitivityQuantitative lociPlatelet traitsMK developmentTranscript levelsCausal SNPsHypersensitive regionARHGEF3Human phenotypesAssociation studiesGenetic studiesHematopoietic subpopulationsGenetic variantsSNPs
2016
Adult human megakaryocyte-erythroid progenitors are in the CD34+CD38mid fraction
Sanada C, Xavier-Ferrucio J, Lu YC, Min E, Zhang PX, Zou S, Kang E, Zhang M, Zerafati G, Gallagher PG, Krause DS. Adult human megakaryocyte-erythroid progenitors are in the CD34+CD38mid fraction. Blood 2016, 128: 923-933. PMID: 27268089, PMCID: PMC4990855, DOI: 10.1182/blood-2016-01-693705.Peer-Reviewed Original ResearchConceptsMegakaryocyte/erythroid progenitorsComparative expression analysisNovel enrichment strategyMegakaryocyte-erythroid progenitorsPurification strategySingle-cell levelShort hairpin RNAFate decisionsE lineageNovel purification strategyLineage fateLineage commitmentGranulocyte colony-stimulating factor-mobilized peripheral bloodMK lineageExpression analysisE progenitorsErythroid lineageFactor-mobilized peripheral bloodDifferential expressionES cellsErythroid progenitorsMYB knockdownHairpin RNALineagesColony-forming unitsLeukaemia-associated Rho guanine nucleotide exchange factor (LARG) plays an agonist specific role in platelet function through RhoA activation
Zou S, Teixeira AM, Yin M, Xiang Y, Xavier-Ferrucio J, Zhang PX, Hwa J, Min W, Krause DS. Leukaemia-associated Rho guanine nucleotide exchange factor (LARG) plays an agonist specific role in platelet function through RhoA activation. Thrombosis And Haemostasis 2016, 116: 506-516. PMID: 27345948, PMCID: PMC5845781, DOI: 10.1160/th15-11-0848.Peer-Reviewed Original ResearchConceptsMegakaryocyte maturationPlatelet functionRhoA activationKO plateletsLeukemia-associated Rho guanineΑ-granule releasePlatelet signal transductionSmall molecule-mediated inhibitionExchange factorSignal transductionMyosin light chain phosphorylationRho guanineKO miceBleeding timeHuman megakaryocytesInternal bleedingPlatelet aggregationNormal haemostasisLight chain phosphorylationHuman plateletsVivo assaysPlateletsSpecific roleMiceChain phosphorylation
2015
Regulation of actin polymerization by tropomodulin-3 controls megakaryocyte actin organization and platelet biogenesis
Sui Z, Nowak RB, Sanada C, Halene S, Krause DS, Fowler VM. Regulation of actin polymerization by tropomodulin-3 controls megakaryocyte actin organization and platelet biogenesis. Blood 2015, 126: 520-530. PMID: 25964668, PMCID: PMC4513252, DOI: 10.1182/blood-2014-09-601484.Peer-Reviewed Original ResearchMeSH KeywordsActin CytoskeletonAnimalsApoptosisBlood PlateletsBlotting, WesternCell MembraneCell ProliferationCells, CulturedCytoplasmEmbryo, MammalianFemaleFluorescent Antibody TechniqueHematopoiesisHemorrhageImmunoprecipitationMegakaryocytesMiceMice, KnockoutMicroscopy, ConfocalMicroscopy, Electron, TransmissionMicroscopy, FluorescencePloidiesPolymerizationTropomodulinConceptsPlatelet biogenesisDemarcation membrane systemF-actinTropomodulin-3Organelle distributionProplatelet formationActin polymerizationF-actin cappingF-actin organizationF-actin cytoskeletonWild-type megakaryocytesActin cytoskeletonActin organizationMK differentiationTmod isoformsLarge proplateletsBiogenesisContractile bundlesActin filamentsDMS formationBinds tropomyosinBud sizeMK numberConfocal microscopyCytoskeleton
2013
Molecular Pathways: Induction of Polyploidy as a Novel Differentiation Therapy for Leukemia
Krause DS, Crispino JD. Molecular Pathways: Induction of Polyploidy as a Novel Differentiation Therapy for Leukemia. Clinical Cancer Research 2013, 19: 6084-6088. PMID: 23963861, PMCID: PMC3836832, DOI: 10.1158/1078-0432.ccr-12-2604.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaAcute megakaryocytic leukemiaAcute promyelocytic leukemiaDifferentiation therapyForms of AMLSpecific hematologic malignanciesAbnormal hematopoietic cellsTrans retinoic acidPolyploidy inducersTumor burdenMyelodysplastic syndromeHematologic malignanciesEffective therapyInduction of polyploidizationMyeloid leukemiaClinical studiesPromyelocytic leukemiaMegakaryocytic leukemiaPrimary myelofibrosisTherapyLeukemiaDifferentiation of megakaryocytesRetinoic acidMalignancySuch agents
2012
Induction of megakaryocyte differentiation drives nuclear accumulation and transcriptional function of MKL1 via actin polymerization and RhoA activation
Smith EC, Teixeira AM, Chen RC, Wang L, Gao Y, Hahn KL, Krause DS. Induction of megakaryocyte differentiation drives nuclear accumulation and transcriptional function of MKL1 via actin polymerization and RhoA activation. Blood 2012, 121: 1094-1101. PMID: 23243284, PMCID: PMC3575755, DOI: 10.1182/blood-2012-05-429993.Peer-Reviewed Original ResearchMeSH KeywordsActinsAnimalsCell DifferentiationCell Line, TumorCell NucleusDNA-Binding ProteinsEnzyme ActivationHumansMegakaryocyte Progenitor CellsMegakaryocytesMiceOncogene Proteins, FusionProtein MultimerizationRhoA GTP-Binding ProteinSerum Response FactorTetradecanoylphorbol AcetateThrombopoietinTrans-ActivatorsConceptsMegakaryocyte differentiationActin polymerizationSubcellular localizationSerum response factor (SRF) transcriptional activityRhoA activitySRF target genesComplex cellular responsesFactor transcriptional activityMuscle cell typesCell-type specificHuman erythroleukemia cellsPrimary megakaryocytesTranscriptional regulatorsActin organizationCellular functionsTranscriptional functionSRF activityNuclear localizationTarget genesMegakaryocytic differentiationTranscriptional activityNuclear accumulationErythroleukemia cellsMolecular mechanismsRhoA activationMKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation
Smith EC, Thon JN, Devine MT, Lin S, Schulz VP, Guo Y, Massaro SA, Halene S, Gallagher P, Italiano JE, Krause DS. MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation. Blood 2012, 120: 2317-2329. PMID: 22806889, PMCID: PMC3447785, DOI: 10.1182/blood-2012-04-420828.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine DiphosphateAnimalsBleeding TimeBlood PlateletsBone Marrow CellsCells, CulturedCrosses, GeneticCytoplasmCytoskeletonGene Expression ProfilingHematopoiesisMegakaryocytesMiceMice, Inbred C57BLMice, KnockoutOligonucleotide Array Sequence AnalysisPlatelet ActivationThrombocytopeniaTrans-ActivatorsTranscription FactorsConceptsMegakaryocyte maturationPlatelet formationSerum response factorSerum response factor expressionMembrane organizationGene expressionMKL1MKL2Response factorDKO miceKO backgroundMegakaryocyte compartmentMegakaryocytesCritical roleMegakaryocyte ploidyExpressionMaturationKnockout miceFactor expressionCrucial roleHomologuesGenesMiceProlonged bleeding timeRoleRole of RhoA-Specific Guanine Exchange Factors in Regulation of Endomitosis in Megakaryocytes
Gao Y, Smith E, Ker E, Campbell P, Cheng EC, Zou S, Lin S, Wang L, Halene S, Krause DS. Role of RhoA-Specific Guanine Exchange Factors in Regulation of Endomitosis in Megakaryocytes. Developmental Cell 2012, 22: 573-584. PMID: 22387001, PMCID: PMC3306542, DOI: 10.1016/j.devcel.2011.12.019.Peer-Reviewed Original ResearchConceptsGEF-H1Efficient platelet productionExchange factor GEF-H1Guanine exchange factorGEF-H1 knockdownDevelopment of aneuploidyGEF-H1 expressionMK polyploidizationExchange factorPloidy defectsAberrant mitosisDevelopmental processesExogenous expressionPolyploidizationRhoA activationEndomitotic cyclePrimary cellsUnknown mechanismMechanistic insightsECT2EndomitosisAneuploid cancersPlatelet productionMegakaryocytesDownregulationProxTom Lymphatic Vessel Reporter Mice Reveal Prox1 Expression in the Adrenal Medulla, Megakaryocytes, and Platelets
Truman LA, Bentley KL, Smith EC, Massaro SA, Gonzalez DG, Haberman AM, Hill M, Jones D, Min W, Krause DS, Ruddle NH. ProxTom Lymphatic Vessel Reporter Mice Reveal Prox1 Expression in the Adrenal Medulla, Megakaryocytes, and Platelets. American Journal Of Pathology 2012, 180: 1715-1725. PMID: 22310467, PMCID: PMC3349900, DOI: 10.1016/j.ajpath.2011.12.026.Peer-Reviewed Original ResearchMeSH KeywordsAdrenal MedullaAnimalsBlood PlateletsCells, CulturedCytoplasmEndothelial CellsGene Expression RegulationGenotypeGlycoproteinsHomeodomain ProteinsLuminescent ProteinsLymph NodesLymphatic VesselsMegakaryocytesMembrane Transport ProteinsMiceMice, Inbred C57BLMice, TransgenicMicroscopy, FluorescenceTumor Cells, CulturedTumor Suppressor ProteinsConceptsLymph nodesLymphatic vesselsAdrenal medullaExpression of Prox1Tumor metastasisHigh endothelial venulesProx1 expressionTwo-photon laser scanning microscopyTransplant rejectionDentate gyrusEndothelial venulesAntigen presentationC57BL/6 backgroundTransgenic miceLipid metabolismMiceNeuroendocrine cellsAdult liverNovel siteMetastasisMedullaStudy of diseasesLiving mouseUnknown rolePotential utility
2010
Discovery that polyploid cells can undergo mitosis
Gao Y, Krause D. Discovery that polyploid cells can undergo mitosis. Cell Cycle 2010, 9: 2491-2501. PMID: 20647753, DOI: 10.4161/cc.9.13.12325.Peer-Reviewed Original ResearchSerum response factor is an essential transcription factor in megakaryocytic maturation
Halene S, Gao Y, Hahn K, Massaro S, Italiano JE, Schulz V, Lin S, Kupfer GM, Krause DS. Serum response factor is an essential transcription factor in megakaryocytic maturation. Blood 2010, 116: 1942-1950. PMID: 20525922, PMCID: PMC3173990, DOI: 10.1182/blood-2010-01-261743.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBleeding TimeBlood PlateletsBone Marrow CellsCell DifferentiationCell LineageCells, CulturedCytoskeletonFemaleFlow CytometryGene Expression ProfilingLuminescent ProteinsMaleMegakaryocytesMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMicroscopy, Electron, TransmissionPlatelet CountPlatelet Factor 4Reverse Transcriptase Polymerase Chain ReactionSerum Response FactorThrombocytopeniaTranscription FactorsConceptsSerum response factorCytoskeletal genesTranscription factorsMADS-box transcription factorsRole of SRFNormal megakaryocyte maturationAbnormal actin distributionResponse factorEssential transcription factorNormal Mendelian frequencyMegakaryocyte developmentMuscle differentiationPF4-Cre miceStress fibersMegakaryocyte maturationMegakaryocytic maturationActin distributionMegakaryocytic lineageMendelian frequencyMegakaryocyte progenitorsVivo assaysCFU-MKGenesPlatelet productionCritical role
2009
Role for MKL1 in megakaryocytic maturation
Cheng EC, Luo Q, Bruscia EM, Renda MJ, Troy JA, Massaro SA, Tuck D, Schulz V, Mane SM, Berliner N, Sun Y, Morris SW, Qiu C, Krause DS. Role for MKL1 in megakaryocytic maturation. Blood 2009, 113: 2826-2834. PMID: 19136660, PMCID: PMC2661865, DOI: 10.1182/blood-2008-09-180596.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood Cell CountBone MarrowCell DifferentiationCell Line, TumorCells, CulturedDNA-Binding ProteinsGene Expression ProfilingGene Expression RegulationHumansLeukemia, Erythroblastic, AcuteMegakaryocytesMiceMice, Inbred C57BLMice, KnockoutOligonucleotide Array Sequence AnalysisOncogene Proteins, FusionPloidiesRecombinant Fusion ProteinsRNA InterferenceRNA, Small InterferingSerum Response FactorThrombocytopeniaThrombopoiesisThrombopoietinTrans-ActivatorsConceptsMegakaryoblastic leukemia 1Reduced platelet countsSerum response factorMegakaryocytic differentiationPeripheral bloodPlatelet countMKL1 expressionMegakaryoblastic leukemiaBone marrow megakaryocytesMuscle cellsPresence of thrombopoietinPhysiologic maturationHuman erythroleukemia cell lineIncreased numberMarrow megakaryocytesCell linesErythroleukemia cell lineMegakaryocytesMegakaryocytic maturationDifferentiated muscle cellsOverexpressionConcurrent increaseMuscle differentiationCellsMaturation
2001
Xenotransplantation of immunodeficient mice with mobilized human blood CD34+ cells provides an in vivo model for human megakaryocytopoiesis and platelet production
Perez L, Rinder H, Wang C, Tracey J, Maun N, Krause D. Xenotransplantation of immunodeficient mice with mobilized human blood CD34+ cells provides an in vivo model for human megakaryocytopoiesis and platelet production. Blood 2001, 97: 1635-1643. PMID: 11238102, DOI: 10.1182/blood.v97.6.1635.Peer-Reviewed Original ResearchConceptsPeripheral blood stem cellsHuman peripheral blood stem cellsPlatelet productionVivo modelStudy of megakaryocytopoiesisCFU-MKHuman megakaryocytopoiesisImmunodeficient miceBone marrowHuman plateletsExogenous cytokinesNOD/SCID miceHuman hematopoiesisBlood stem cellsHuman cell engraftmentPlatelet developmentNonobese diabetic/Lymphoid lineageStem cellsHuman blood CD34MegakaryocytopoiesisPeripheral bloodCytokine stimulationMurine recipientsThrombin stimulation