{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T16:39:44Z","timestamp":1772210384321,"version":"3.50.1"},"reference-count":70,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000900","name":"California Institute for Regenerative Medicine","doi-asserted-by":"publisher","award":["DISC1-08776"],"award-info":[{"award-number":["DISC1-08776"]}],"id":[{"id":"10.13039\/100000900","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DP2 HL141006"],"award-info":[{"award-number":["DP2 HL141006"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007421","name":"Li Ka Shing Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007421","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014221","name":"Heritage Medical Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014221","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Myeloproliferative neoplasms (MPNs) cause the over-production of blood cells such as erythrocytes (polycythemia vera) or platelets (essential thrombocytosis). JAK2 V617F is the most prevalent somatic mutation in many MPNs, but previous modeling of this mutation in mice relied on transgenic overexpression and resulted in diverse phenotypes that were in some cases attributed to expression level. CRISPR-Cas9 engineering offers new possibilities to model and potentially cure genetically encoded disorders via precise modification of the endogenous locus in primary cells. Here we develop \u201cscarless\u201d Cas9-based reagents to create and reverse the JAK2 V617F mutation in an immortalized human erythroid progenitor cell line (HUDEP-2), CD34+ adult human hematopoietic stem and progenitor cells (HSPCs), and immunophenotypic long-term hematopoietic stem cells (LT-HSCs). We find no overt\n                    <jats:italic>in vitro<\/jats:italic>\n                    increase in proliferation associated with an endogenous JAK2 V617F allele, but co-culture with wild type cells unmasks a competitive growth advantage provided by the mutation. Acquisition of the V617F allele also promotes terminal differentiation of erythroid progenitors, even in the absence of hematopoietic cytokine signaling. Taken together, these data are consistent with the gradually progressive manifestation of MPNs and reveals that endogenously acquired JAK2 V617F mutations may yield more subtle phenotypes as compared to transgenic overexpression models.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0247858","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T13:49:32Z","timestamp":1614865772000},"page":"e0247858","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Genome editing to model and reverse a prevalent mutation associated with myeloproliferative neoplasms"],"prefix":"10.1371","volume":"16","author":[{"given":"Ron","family":"Baik","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stacia K.","family":"Wyman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaheen","family":"Kabir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2458-0121","authenticated-orcid":true,"given":"Jacob E.","family":"Corn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"pone.0247858.ref001","first-page":"9","article-title":"Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1","author":"G Schiroli","year":"2017","journal-title":"Sci Transl Med"},{"key":"pone.0247858.ref002","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1182\/blood-2016-01-678128","article-title":"Customizing the genome as therapy for the 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polycythemia vera, essential thrombocythemia, and primary myelofibrosis","volume":"4","author":"J Thiele","year":"2009","journal-title":"Curr Hematol Malig Rep"},{"key":"pone.0247858.ref006","doi-asserted-by":"crossref","first-page":"3842","DOI":"10.1002\/cncr.24440","article-title":"The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos","volume":"115","author":"A Tefferi","year":"2009","journal-title":"Cancer"},{"key":"pone.0247858.ref007","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1182\/blood-2016-10-695940","article-title":"Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms","volume":"129","author":"W Vainchenker","year":"2017","journal-title":"Blood"},{"key":"pone.0247858.ref008","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1056\/NEJMoa051113","article-title":"A gain-of-function mutation of JAK2 in myeloproliferative disorders","volume":"352","author":"R Kralovics","year":"2005","journal-title":"N Engl J Med"},{"key":"pone.0247858.ref009","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1038\/nature03546","article-title":"A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera","volume":"434","author":"C James","year":"2005","journal-title":"Nature"},{"key":"pone.0247858.ref010","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.ccr.2005.03.023","article-title":"Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis","volume":"7","author":"RL Levine","year":"2005","journal-title":"Cancer Cell"},{"key":"pone.0247858.ref011","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(05)71142-9","article-title":"Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders","volume":"365","author":"EJ Baxter","year":"2005","journal-title":"Lancet"},{"issue":"Suppl 5","key":"pone.0247858.ref012","doi-asserted-by":"crossref","first-page":"v85","DOI":"10.1093\/annonc\/mdv203","article-title":"Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"26","author":"AM Vannucchi","year":"2015","journal-title":"Ann Oncol"},{"key":"pone.0247858.ref013","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1001\/jamaoncol.2015.89","article-title":"Myeloproliferative neoplasms: A contemporary review","volume":"1","author":"A Tefferi","year":"2015","journal-title":"JAMA Oncol"},{"key":"pone.0247858.ref014","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1182\/blood-2015-03-635235","article-title":"The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis","volume":"126","author":"M Deininger","year":"2015","journal-title":"Blood"},{"key":"pone.0247858.ref015","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.hoc.2014.08.003","article-title":"Role of hematopoietic stem cell transplantation in patients with myeloproliferative disease","volume":"28","author":"RB Salit","year":"2014","journal-title":"Hematol Oncol Clin North Am"},{"key":"pone.0247858.ref016","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1600-065X.2008.00754.x","article-title":"Janus kinases in immune cell signaling","volume":"228","author":"K Ghoreschi","year":"2009","journal-title":"Immunol Rev"},{"key":"pone.0247858.ref017","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nrm909","article-title":"Stats: transcriptional control and biological impact","volume":"3","author":"DE Levy","year":"2002","journal-title":"Nat Rev Mol Cell 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Biotechnol"},{"key":"pone.0247858.ref036","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/nbt.2647","article-title":"DNA targeting specificity of RNA-guided Cas9 nucleases","volume":"31","author":"PD Hsu","year":"2013","journal-title":"Nat Biotechnol"},{"key":"pone.0247858.ref037","doi-asserted-by":"crossref","first-page":"e59890","DOI":"10.1371\/journal.pone.0059890","article-title":"Establishment of immortalized human erythroid progenitor cell lines able to produce enucleated red blood cells","volume":"8","author":"R Kurita","year":"2013","journal-title":"PLoS One"},{"key":"pone.0247858.ref038","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0092-8674(93)90415-M","article-title":"Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase","volume":"74","author":"LS 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Role of receptor phosphorylation in erythropoietin signal transduction","volume":"271","author":"ST Sawyer","year":"1996","journal-title":"J Biol Chem"},{"key":"pone.0247858.ref041","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/S1043-2760(98)00101-5","article-title":"The erythropoietin receptor: structure, activation and intracellular signal transduction","volume":"10","author":"SN Constantinescu","year":"1999","journal-title":"Trends in Endocrinology & Metabolism"},{"key":"pone.0247858.ref042","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/stem.2935","article-title":"Improving gene editing outcomes in human hematopoietic stem and progenitor cells by temporal control of DNA repair","volume":"37","author":"A Lomova","year":"2018","journal-title":"Stem Cells"},{"key":"pone.0247858.ref043","article-title":"Controlled cycling and quiescence enables homology directed repair in engraftment-enriched adult hematopoietic stem and progenitor cells","author":"J Shin","year":"2018","journal-title":"BioRxiv"},{"key":"pone.0247858.ref044","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/nature13420","article-title":"Targeted genome editing in human repopulating haematopoietic stem cells","volume":"510","author":"P Genovese","year":"2014","journal-title":"Nature"},{"key":"pone.0247858.ref045","author":"I Fares","year":"2014","journal-title":"Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal"},{"key":"pone.0247858.ref046","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.omtn.2018.04.017","article-title":"Priming human repopulating hematopoietic stem and progenitor cells for cas9\/sgrna gene targeting","volume":"12","author":"CT Charlesworth","year":"2018","journal-title":"Mol Ther Nucleic Acids"},{"key":"pone.0247858.ref047","doi-asserted-by":"crossref","first-page":"360ra134","DOI":"10.1126\/scitranslmed.aaf9336","article-title":"Selection-free genome editing of the sickle 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Yan","year":"2012","journal-title":"Blood"},{"key":"pone.0247858.ref060","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/s41586-019-1367-0","article-title":"Somatic mutations and cell identity linked by Genotyping of Transcriptomes","volume":"571","author":"AS Nam","year":"2019","journal-title":"Nature"},{"key":"pone.0247858.ref061","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1046\/j.1365-2141.2002.03386.x","article-title":"Serum erythropoietin values in erythrocytoses and in primary thrombocythaemia","volume":"117","author":"M Messinezy","year":"2002","journal-title":"Br J Haematol"},{"key":"pone.0247858.ref062","first-page":"1194","article-title":"Diagnostic value of serum erythropoietin level in patients with absolute erythrocytosis","volume":"89","author":"P Mossuz","year":"2004","journal-title":"Haematologica"},{"key":"pone.0247858.ref063","first-page":"217","article-title":"Low serum erythropoietin\u2014a strong diagnostic criterion of primary polycythaemia even at normal haemoglobin levels","volume":"17","author":"M Messinezy","year":"1995","journal-title":"Clin Lab Haematol"},{"key":"pone.0247858.ref064","first-page":"2014","article-title":"Elevated serum erythropoietin in a patient with polycythaemia vera presenting with Budd-Chiari syndrome","author":"C Jones","year":"2014","journal-title":"BMJ Case Rep"},{"key":"pone.0247858.ref065","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.stemcr.2016.08.005","article-title":"Improved Human Erythropoiesis and Platelet Formation in Humanized NSGW41","volume":"7","author":"S Rahmig","year":"2016","journal-title":"Mice. Stem Cell Rep"},{"key":"pone.0247858.ref066","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1097\/MOH.0000000000000385","article-title":"The changing landscape of gene editing in hematopoietic stem cells: a step towards Cas9 clinical translation","volume":"24","author":"DP Dever","year":"2017","journal-title":"Curr Opin Hematol"},{"key":"pone.0247858.ref067","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/nbt.1663","article-title":"Human hematopoietic stem\/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo","volume":"28","author":"N Holt","year":"2010","journal-title":"Nat Biotechnol"},{"key":"pone.0247858.ref068","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.1016\/j.celrep.2018.04.103","article-title":"Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome","volume":"23","author":"CY Kuo","year":"2018","journal-title":"Cell Rep"},{"key":"pone.0247858.ref069","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.omtm.2016.12.009","article-title":"Long-Term Engraftment and Fetal Globin Induction upon BCL11A Gene Editing in Bone-Marrow-Derived CD34+ Hematopoietic Stem and Progenitor Cells","volume":"4","author":"K-H Chang","year":"2017","journal-title":"Mol Ther Methods Clin Dev"},{"key":"pone.0247858.ref070","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1126\/science.1256337","article-title":"Cord blood expansion. 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