File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia

TitleJAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia
Authors
Issue Date2010
Citation
Blood, 2010, v. 116, n. 9, p. 1528-1538 How to Cite?
AbstractThe JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and is sufficient to produce a myeloproliferative phenotype in murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease phenotype is influenced by the level of mutant JAK2 signaling, and we have therefore generated a conditional knock-in mouse in which a human JAK2 V617F is expressed under the control of the mouse Jak2 locus. Human and murine Jak2 transcripts are expressed at similar levels, and mice develop modest increases in hemoglobin and platelet levels reminiscent of human JAK2 V617F-positive essential thrombocythemia. The phenotype is transplantable and accompanied by increased terminal erythroid and megakaryocyte differentiation together with increased numbers of clonogenic progenitors, including erythropoietin-independent erythroid colonies. Unexpectedly, JAK2 V617F mice develop reduced numbers of lineage-Sca-1 + c-Kit + cells, which exhibit increased DNA damage, reduced apoptosis, and reduced cell cycling. Moreover, competitive bone marrow transplantation studies demonstrated impaired hematopoietic stem cell function in JAK2 V617F mice. These results suggest that the chronicity of human myeloproliferative neoplasms may reflect a balance between impaired hematopoietic stem cell function and the accumulation of additional mutations. © 2010 by The American Society of Hematology.
Persistent Identifierhttp://hdl.handle.net/10722/249040
ISSN
2023 Impact Factor: 21.0
2023 SCImago Journal Rankings: 5.272
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLi, Juan-
dc.contributor.authorSpensberger, Dominik-
dc.contributor.authorAhn, Jong Sook-
dc.contributor.authorAnand, Shubha-
dc.contributor.authorBeer, Philip A.-
dc.contributor.authorGhevaert, Cedric-
dc.contributor.authorChen, Edwin-
dc.contributor.authorForrai, Ariel-
dc.contributor.authorScott, Linda M.-
dc.contributor.authorFerreira, Rita-
dc.contributor.authorCampbell, Peter J.-
dc.contributor.authorWatson, Steve P.-
dc.contributor.authorLiu, Pentao-
dc.contributor.authorErber, Wendy N.-
dc.contributor.authorHuntly, Brian J.P.-
dc.contributor.authorOttersbach, Katrin-
dc.contributor.authorGreen, Anthony R.-
dc.date.accessioned2017-10-27T05:58:56Z-
dc.date.available2017-10-27T05:58:56Z-
dc.date.issued2010-
dc.identifier.citationBlood, 2010, v. 116, n. 9, p. 1528-1538-
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/249040-
dc.description.abstractThe JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and is sufficient to produce a myeloproliferative phenotype in murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease phenotype is influenced by the level of mutant JAK2 signaling, and we have therefore generated a conditional knock-in mouse in which a human JAK2 V617F is expressed under the control of the mouse Jak2 locus. Human and murine Jak2 transcripts are expressed at similar levels, and mice develop modest increases in hemoglobin and platelet levels reminiscent of human JAK2 V617F-positive essential thrombocythemia. The phenotype is transplantable and accompanied by increased terminal erythroid and megakaryocyte differentiation together with increased numbers of clonogenic progenitors, including erythropoietin-independent erythroid colonies. Unexpectedly, JAK2 V617F mice develop reduced numbers of lineage-Sca-1 + c-Kit + cells, which exhibit increased DNA damage, reduced apoptosis, and reduced cell cycling. Moreover, competitive bone marrow transplantation studies demonstrated impaired hematopoietic stem cell function in JAK2 V617F mice. These results suggest that the chronicity of human myeloproliferative neoplasms may reflect a balance between impaired hematopoietic stem cell function and the accumulation of additional mutations. © 2010 by The American Society of Hematology.-
dc.languageeng-
dc.relation.ispartofBlood-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleJAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1182/blood-2009-12-259747-
dc.identifier.pmid20489053-
dc.identifier.scopuseid_2-s2.0-77956578342-
dc.identifier.volume116-
dc.identifier.issue9-
dc.identifier.spage1528-
dc.identifier.epage1538-
dc.identifier.eissn1528-0020-
dc.identifier.isiWOS:000281572700021-
dc.identifier.issnl0006-4971-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats