{"id":"https://openalex.org/W4310127306","doi":"https://doi.org/10.1182/blood-2022-165335","title":"Using a Humanized Animal Model to Determine the Minimum JAK2V617F Mutant Allele Burden Required to Generate MPN Pathologies","display_name":"Using a Humanized Animal Model to Determine the Minimum JAK2V617F Mutant Allele Burden Required to Generate MPN Pathologies","publication_year":2022,"publication_date":"2022-11-15","ids":{"openalex":"https://openalex.org/W4310127306","doi":"https://doi.org/10.1182/blood-2022-165335"},"language":"en","primary_location":{"id":"doi:10.1182/blood-2022-165335","doi":"https://doi.org/10.1182/blood-2022-165335","is_oa":false,"landing_page_url":"https://doi.org/10.1182/blood-2022-165335","pdf_url":null,"source":{"id":"https://openalex.org/S200071133","display_name":"Blood","issn_l":"0006-4971","issn":["0006-4971","1528-0020"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["anvur-scientific","cwts-core","dongbi-a","doyens","jufo-3","ki-jl-3","medline","norway-2","poland-200","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320990","host_organization_name":"Elsevier BV","host_organization_lineage":["https://openalex.org/P4310320990"],"host_organization_lineage_names":["Elsevier BV"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Blood","raw_type":"journal-article"},"volume":null,"type":"article","indexed_in":["crossref"],"open_access":{"is_oa":false,"oa_status":"closed","oa_url":null,"any_repository_has_fulltext":false},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5036584353","display_name":"Tyler M. Parsons","orcid":"https://orcid.org/0000-0003-0277-1557","observed_orcids":["https://orcid.org/0000-0003-0277-1557"]},"institutions":[{"id":"https://openalex.org/I204465549","display_name":"Washington University in St. Louis","ror":"https://ror.org/01yc7t268","country_code":"US","type":"education","lineage":["https://openalex.org/I204465549"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Tyler M. Parsons","raw_affiliation_strings":["1Division of Oncology, Washington University School of Medicine, St. Louis, MO"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"1Division of Oncology, Washington University School of Medicine, St. Louis, MO","institution_ids":["https://openalex.org/I204465549"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5019612246","display_name":"Aishwarya Krishnan","orcid":"https://orcid.org/0000-0001-6191-5966","observed_orcids":["https://orcid.org/0000-0001-6191-5966"]},"institutions":[{"id":"https://openalex.org/I204465549","display_name":"Washington University in St. Louis","ror":"https://ror.org/01yc7t268","country_code":"US","type":"education","lineage":["https://openalex.org/I204465549"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Aishwarya Krishnan","raw_affiliation_strings":["2Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"2Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO","institution_ids":["https://openalex.org/I204465549"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5103221389","display_name":"Wentao Han","orcid":"https://orcid.org/0000-0003-4395-9441","observed_orcids":["https://orcid.org/0000-0003-4395-9441"]},"institutions":[{"id":"https://openalex.org/I204465549","display_name":"Washington University in St. Louis","ror":"https://ror.org/01yc7t268","country_code":"US","type":"education","lineage":["https://openalex.org/I204465549"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Wentao Han","raw_affiliation_strings":["3Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"3Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO","institution_ids":["https://openalex.org/I204465549"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5081128399","display_name":"Andrew L. Young","orcid":"https://orcid.org/0000-0001-7698-3267","observed_orcids":["https://orcid.org/0000-0001-7698-3267"]},"institutions":[{"id":"https://openalex.org/I204465549","display_name":"Washington University in St. Louis","ror":"https://ror.org/01yc7t268","country_code":"US","type":"education","lineage":["https://openalex.org/I204465549"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Andrew L Young","raw_affiliation_strings":["4Department of Medicine, Division of Oncology, Washington University School of Medicine In St. Louis, Saint Louis, MO"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"4Department of Medicine, Division of Oncology, Washington University School of Medicine In St. Louis, Saint Louis, MO","institution_ids":["https://openalex.org/I204465549"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5066248565","display_name":"Grant Anthony Challen","orcid":"https://orcid.org/0000-0003-4669-8814","observed_orcids":["https://orcid.org/0000-0003-4669-8814"]},"institutions":[{"id":"https://openalex.org/I204465549","display_name":"Washington University in St. Louis","ror":"https://ror.org/01yc7t268","country_code":"US","type":"education","lineage":["https://openalex.org/I204465549"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Grant A Challen","raw_affiliation_strings":["5Division of Oncology, Washington University School of Medicine, St. Louis, MO"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"5Division of Oncology, Washington University School of Medicine, St. Louis, MO","institution_ids":["https://openalex.org/I204465549"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":1,"corresponding_author_ids":[],"corresponding_institution_ids":["https://openalex.org/I204465549"],"apc_list":{"value":2500,"currency":"USD","value_usd":2500},"apc_paid":null,"fwci":0.0,"has_fulltext":false,"cited_by_count":0,"citation_normalized_percentile":{"value":0.22980925,"is_in_top_1_percent":false,"is_in_top_10_percent":false},"cited_by_percentile_year":null,"biblio":{"volume":"140","issue":"Supplement 1","first_page":"6744","last_page":"6745"},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T11628","display_name":"Myeloproliferative Neoplasms: Diagnosis and Treatment","score":1.0,"subfield":{"id":"https://openalex.org/subfields/2716","display_name":"Genetics"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},"topics":[{"id":"https://openalex.org/T11628","display_name":"Myeloproliferative Neoplasms: Diagnosis and Treatment","score":1.0,"subfield":{"id":"https://openalex.org/subfields/2716","display_name":"Genetics"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T10746","display_name":"Platelet Disorders and Treatments","score":0.0,"subfield":{"id":"https://openalex.org/subfields/2720","display_name":"Hematology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T10309","display_name":"Acute Myeloid Leukemia Research","score":0.0,"subfield":{"id":"https://openalex.org/subfields/2720","display_name":"Hematology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/myeloproliferative-neoplasms","display_name":"myeloproliferative neoplasms","score":0.9580000042915344},{"id":"https://openalex.org/keywords/jak2-v617f-mutation","display_name":"JAK2 V617F mutation","score":0.9010000228881836},{"id":"https://openalex.org/keywords/variant-allele-frequency","display_name":"variant allele frequency","score":0.9480000138282776},{"id":"https://openalex.org/keywords/humanized-mouse-model","display_name":"humanized mice","score":0.8270000219345093},{"id":"https://openalex.org/keywords/hematopoietic-stem-cells","display_name":"hematopoietic stem cells","score":0.7829999923706055},{"id":"https://openalex.org/keywords/cd34-cells","display_name":"CD34+ cells","score":0.7609999775886536},{"id":"https://openalex.org/keywords/crispr-cas9","display_name":"CRISPR/Cas9","score":0.5550000071525574},{"id":"https://openalex.org/keywords/homology-directed-repair","display_name":"homology-directed repair","score":0.8619999885559082},{"id":"https://openalex.org/keywords/polycythemia-vera","display_name":"polycythemia vera","score":0.8550000190734863},{"id":"https://openalex.org/keywords/essential-thrombocythemia","display_name":"essential thrombocythemia","score":0.9610000252723694},{"id":"https://openalex.org/keywords/myelofibrosis","display_name":"myelofibrosis","score":0.9990000128746033}],"concepts":[{"id":"https://openalex.org/C2781057849","wikidata":"https://www.wikidata.org/wiki/Q1368780","display_name":"Essential thrombocythemia","level":3,"score":0.6058251857757568},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.5957233905792236},{"id":"https://openalex.org/C2780076729","wikidata":"https://www.wikidata.org/wiki/Q1752571","display_name":"Myelofibrosis","level":3,"score":0.5434011816978455},{"id":"https://openalex.org/C2779282312","wikidata":"https://www.wikidata.org/wiki/Q1956561","display_name":"Myeloid","level":2,"score":0.5260957479476929},{"id":"https://openalex.org/C2780007613","wikidata":"https://www.wikidata.org/wiki/Q546523","display_name":"Bone marrow","level":2,"score":0.49202486872673035},{"id":"https://openalex.org/C180754005","wikidata":"https://www.wikidata.org/wiki/Q80726","display_name":"Allele","level":3,"score":0.4879752993583679},{"id":"https://openalex.org/C2778837598","wikidata":"https://www.wikidata.org/wiki/Q948318","display_name":"Polycythemia vera","level":2,"score":0.48337358236312866},{"id":"https://openalex.org/C502942594","wikidata":"https://www.wikidata.org/wiki/Q3421914","display_name":"Cancer research","level":1,"score":0.46380236744880676},{"id":"https://openalex.org/C113968399","wikidata":"https://www.wikidata.org/wiki/Q7559241","display_name":"Somatic evolution in cancer","level":3,"score":0.45223280787467957},{"id":"https://openalex.org/C28328180","wikidata":"https://www.wikidata.org/wiki/Q48196","display_name":"Stem cell","level":2,"score":0.4498273432254791},{"id":"https://openalex.org/C203014093","wikidata":"https://www.wikidata.org/wiki/Q101929","display_name":"Immunology","level":1,"score":0.42206841707229614},{"id":"https://openalex.org/C54355233","wikidata":"https://www.wikidata.org/wiki/Q7162","display_name":"Genetics","level":1,"score":0.34771621227264404},{"id":"https://openalex.org/C104317684","wikidata":"https://www.wikidata.org/wiki/Q7187","display_name":"Gene","level":2,"score":0.11277574300765991}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.1182/blood-2022-165335","doi":"https://doi.org/10.1182/blood-2022-165335","is_oa":false,"landing_page_url":"https://doi.org/10.1182/blood-2022-165335","pdf_url":null,"source":{"id":"https://openalex.org/S200071133","display_name":"Blood","issn_l":"0006-4971","issn":["0006-4971","1528-0020"],"is_oa":false,"is_in_doaj":false,"is_core":true,"listed_in":["anvur-scientific","cwts-core","dongbi-a","doyens","jufo-3","ki-jl-3","medline","norway-2","poland-200","russia-white-list-1","vabb-shw"],"host_organization":"https://openalex.org/P4310320990","host_organization_name":"Elsevier BV","host_organization_lineage":["https://openalex.org/P4310320990"],"host_organization_lineage_names":["Elsevier BV"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Blood","raw_type":"journal-article"}],"best_oa_location":null,"sustainable_development_goals":[{"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being","score":0.9922999739646912}],"sustainable_development_goals_aurora":[{"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being","score":0.7300000190734863}],"study_designs":[],"awards":[],"funders":[],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W2590651773","https://openalex.org/W3208897743","https://openalex.org/W2002968540","https://openalex.org/W7148980700","https://openalex.org/W2554472954","https://openalex.org/W2980416526","https://openalex.org/W2118555215","https://openalex.org/W4405044436","https://openalex.org/W2054792541","https://openalex.org/W4387115851"],"abstract_inverted_index":{"Myeloproliferative":[0],"neoplasms":[1],"(MPNs)":[2],"are":[3,55],"clonal":[4],"hematological":[5,198],"diseases":[6],"driven":[7],"by":[8,19,263,350,354],"somatic":[9,72],"mutations":[10],"acquired":[11,71],"in":[12,62,76,153,158,180,254,270,307,407,424,446,451,459,464,472,501,542,630],"hematopoietic":[13],"stem":[14],"cells":[15,104,240,256,287,296,320,405],"(HSCs)":[16],"and":[17,79,92,119,196,216,340,371,383,435,449,456,462,486,539,628],"characterized":[18],"the":[20,63,99,146,165,232,235,266,299,569,574,582,587,617],"deviant,":[21],"unregulated":[22],"proliferation":[23],"of":[24,101,149,163,177,193,238,268,344,402,517,529,536,571,612,619],"one":[25],"or":[26,45,288],"more":[27],"myeloid":[28],"lineages.":[29],"Chronic":[30],"MPN":[31,60,77,97,113,154,187,314,518,523,588,631],"can":[32],"present":[33],"as":[34,82,259],"polycythemia":[35],"vera":[36],"(PV;":[37],"excess":[38,43],"erythrocytes),":[39],"essential":[40],"thrombocythemia":[41],"(ET;":[42],"platelets),":[44],"myelofibrosis":[46],"(MF;":[47],"bone":[48,291],"marrow":[49,292],"fibrosis).":[50],"More":[51],"than":[52,145,398],"300,000":[53],"patients":[54,78,181],"currently":[56,132],"living":[57],"with":[58,87,115,182,532,601],"an":[59,70,112],"diagnosis":[61],"United":[64],"States.":[65],"The":[66,127,175,274,331],"JAK2V617F":[67,102,184,269,309,409,422,474,503,530,572,622],"variant":[68,123],"is":[69,80,108,131,142,188,304],"mutation":[73,249],"recurrently":[74],"found":[75,152],"used":[81],"a":[83,139,159,206,222,246,260,305,312,513,521,526,533,543],"diagnostic":[84],"marker":[85],"along":[86],"increased":[88,90,406,500],"hematocrit,":[89,378,537],"hemoglobin,":[91,379,538],"adverse":[93],"thrombotic":[94],"events.":[95],"In":[96,244,494,551],"patients,":[98],"frequency":[100,125],"mutant":[103,167,345,351],"varies":[105],"widely":[106],"but":[107],"known":[109],"to":[110,190,230,257,297,337,364,415,431,477,506,548,559,586,590,598,610,625],"induce":[111],"phenotype":[114,524,589],"both":[116,408,433,442,473,502],"high":[117,613],"(>50%)":[118],"very":[120,160],"low":[121,183,242,308,332,527,560,565,621],"(<5%)":[122],"allelic":[124],"(VAF).":[126],"reason":[128],"for":[129,171],"this":[130,194,201,608],"unknown.":[133],"Most":[134],"JAK2-mutant":[135],"animal":[136],"models":[137,600],"model":[138,211,516,546,609],"VAF":[140,185,264,267,310,401,423,528,570,584,604],"which":[141,519],"much":[143,602],"higher":[144,603],"lower":[147,595],"end":[148],"detectable":[150],"VAFs":[151],"patients.":[155,632],"This":[156,579],"results":[157],"limited":[161],"understanding":[162,176,192],"what":[164],"minimal":[166],"cell":[168,333,367,485,562],"burden":[169,343,353,623],"required":[170],"disease":[172,195,342,626],"manifestation":[173],"is.":[174],"genotype/phenotype":[178],"relationships":[179],"chronic":[186],"paramount":[189],"our":[191],"its":[197],"progression.":[199],"To":[200],"end,":[202],"we":[203,213,553],"have":[204],"designed":[205],"clinically":[207,593],"relevant,":[208],"humanized":[209,544],"mouse":[210,436,545],"wherein":[212],"employ":[214],"CRISPR":[215],"homology":[217],"directed":[218],"repair":[219],"(HDR)":[220],"via":[221,252],"single":[223],"stranded":[224],"oligo":[225],"donor":[226],"nucleotide":[227],"sequence":[228],"(ssODN)":[229],"knock-in":[231],"JAK2V617Fmutation":[233],"at":[234,241,361,592],"endogenous":[236],"locus":[237],"human":[239,366,434],"VAF.":[243],"addition,":[245,495,552],"synonymous":[247],"JAK2V617V":[248,480],"was":[250,335,348],"introduced":[251],"CRISPR/ssODN":[253],"parallel":[255],"serve":[258],"control":[261],"tracked":[262],"alongside":[265],"their":[271,478,507],"corresponding":[272],"cohorts.":[273],"respective":[275,479,508],"ssODNs":[276],"were":[277,321,469,498],"nucleofected":[278],"into":[279,324,616],"either":[280],"umbilical":[281],"cord":[282],"blood":[283,373,381,390,439,484],"(UCB)":[284],"derived":[285,294,437],"CD34+":[286,295,319],"healthy":[289],"adult":[290],"(BM)":[293],"investigate":[298],"possibility":[300],"that":[301,555],"developmental":[302],"age":[303],"variable":[306],"inducing":[311],"clinical":[313,515,614],"phenotype.":[315],"After":[316],"nucleofection,":[317],"20,000":[318],"intra-tibially":[322],"transplanted":[323],"sub-lethally":[325],"irradiated":[326],"(250":[327],"rads)":[328],"NSGS":[329],"mice.":[330],"input":[334,563],"utilized":[336],"limit":[338],"engraftment":[339,392,557],"initial":[341],"cells.":[346,440],"Effect":[347],"measured":[349],"allele":[352],"droplet-digital":[355],"PCR":[356],"(ddPCR)":[357],"analysis,":[358],"flow":[359],"cytometry":[360],"selected":[362],"timepoints":[363],"track":[365],"engraftment,":[368],"spleen":[369,496,540],"weight,":[370],"complete":[372],"count":[374],"(CBC)":[375],"analysis":[376],"including":[377],"white":[380,483],"cells,":[382],"platelets.":[384],"At":[385],"4":[386,567],"months":[387,412],"post-transplant,":[388],"peripheral":[389,438],"hCD45+":[391,404,575],"across":[393],"all":[394],"cohorts":[395,410,448,461,475,504],"averaged":[396],"less":[397],"3%.":[399],"Average":[400],"circulating":[403],"5":[411],"post-transplant":[413],"compared":[414,476,505,547,597],"day":[416],"0":[417],"post":[418],"nucleofection.":[419],"Notably,":[420],"overall":[421,583],"each":[425],"sample":[426],"remained":[427,489],"<5%":[428],"when":[429],"adjusted":[430],"include":[432],"Remarkably,":[441],"hematocrit":[443],"(p=":[444],".037":[445],"UCB":[447,460],"p=.0096":[450],"BM":[452,465],"cohorts;":[453,466],"Figure":[454,467,633],"1A)":[455],"hemoglobin":[457],"(p=.046":[458],"p=.0026":[463],"1B)":[468],"significantly":[470,499],"elevated":[471],"controls,":[481],"while":[482,556],"platelet":[487],"counts":[488],"unchanged":[490],"within":[491,573],"normal":[492],"ranges.":[493],"weights":[497],"controls.":[509,550],"These":[510],"data":[511],"demonstrate":[512,554],"successful":[514],"induces":[520],"classical":[522],"where":[525],"corresponds":[531],"significant":[534],"increase":[535],"weight":[541],"relevant":[549,594],"due":[558],"hCD34+":[561],"remains":[564],"after":[566],"months,":[568],"sub-":[576],"population":[577],"increases.":[578],"successfully":[580],"enables":[581],"contributing":[585],"remain":[591],"levels":[596],"other":[599],"contributions.":[605],"We":[606],"believe":[607],"be":[611],"relevance":[615],"investigation":[618],"how":[620],"relates":[624],"development":[627],"progression":[629],"1View":[634,637],"largeDownload":[635,638],"PPTFigure":[636],"PPT":[639],"Close":[640],"modal":[641]},"counts_by_year":[],"updated_date":"2026-10-16T09:59:22.235173","created_date":"2022-11-30T00:00:00"}