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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Physiological <italic>Jak2V617F</italic> expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells</title><author><name sortKey="Mullally, Ann" sort="Mullally, Ann" uniqKey="Mullally A" first="Ann" last="Mullally">Ann Mullally</name><affiliation><nlm:aff id="A1">Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Lane, Steven W" sort="Lane, Steven W" uniqKey="Lane S" first="Steven W." last="Lane">Steven W. Lane</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A4">University of Queensland, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Ball, Brian" sort="Ball, Brian" uniqKey="Ball B" first="Brian" last="Ball">Brian Ball</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Megerdichian, Christine" sort="Megerdichian, Christine" uniqKey="Megerdichian C" first="Christine" last="Megerdichian">Christine Megerdichian</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Okabe, Rachel" sort="Okabe, Rachel" uniqKey="Okabe R" first="Rachel" last="Okabe">Rachel Okabe</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Al Shahrour, Fatima" sort="Al Shahrour, Fatima" uniqKey="Al Shahrour F" first="Fatima" last="Al-Shahrour">Fatima Al-Shahrour</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Broad Institute, Cambridge, Massachusetts 02142, USA</nlm:aff></affiliation></author><author><name sortKey="Paktinat, Mahnaz" sort="Paktinat, Mahnaz" uniqKey="Paktinat M" first="Mahnaz" last="Paktinat">Mahnaz Paktinat</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Haydu, J Erika" sort="Haydu, J Erika" uniqKey="Haydu J" first="J. Erika" last="Haydu">J. Erika Haydu</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Housman, Elizabeth" sort="Housman, Elizabeth" uniqKey="Housman E" first="Elizabeth" last="Housman">Elizabeth Housman</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Lord, Allegra M" sort="Lord, Allegra M" uniqKey="Lord A" first="Allegra M." last="Lord">Allegra M. Lord</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Wernig, Gerlinde" sort="Wernig, Gerlinde" uniqKey="Wernig G" first="Gerlinde" last="Wernig">Gerlinde Wernig</name><affiliation><nlm:aff id="A5">Department of Pathology, Stanford University, California 94305, USA</nlm:aff></affiliation></author><author><name sortKey="Kharas, Michael G" sort="Kharas, Michael G" uniqKey="Kharas M" first="Michael G." last="Kharas">Michael G. Kharas</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Mercher, Thomas" sort="Mercher, Thomas" uniqKey="Mercher T" first="Thomas" last="Mercher">Thomas Mercher</name><affiliation><nlm:aff id="A6">INSERM U985, Université Paris Descartes, Hôpital Necker, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Kutok, Jeffery L" sort="Kutok, Jeffery L" uniqKey="Kutok J" first="Jeffery L." last="Kutok">Jeffery L. Kutok</name><affiliation><nlm:aff id="A7">Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Gilliland, D Gary" sort="Gilliland, D Gary" uniqKey="Gilliland D" first="D. Gary" last="Gilliland">D. Gary Gilliland</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A8">Merck & Co., North Wales, Pennsylvania 19454, USA</nlm:aff></affiliation></author><author><name sortKey="Ebert, Benjamin L" sort="Ebert, Benjamin L" uniqKey="Ebert B" first="Benjamin L." last="Ebert">Benjamin L. Ebert</name><affiliation><nlm:aff id="A1">Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Broad Institute, Cambridge, Massachusetts 02142, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20541703</idno><idno type="pmc">2909585</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909585</idno><idno type="RBID">PMC:2909585</idno><idno type="doi">10.1016/j.ccr.2010.05.015</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">001428</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001428</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Physiological <italic>Jak2V617F</italic> expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells</title><author><name sortKey="Mullally, Ann" sort="Mullally, Ann" uniqKey="Mullally A" first="Ann" last="Mullally">Ann Mullally</name><affiliation><nlm:aff id="A1">Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Lane, Steven W" sort="Lane, Steven W" uniqKey="Lane S" first="Steven W." last="Lane">Steven W. Lane</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A4">University of Queensland, Brisbane, Australia</nlm:aff></affiliation></author><author><name sortKey="Ball, Brian" sort="Ball, Brian" uniqKey="Ball B" first="Brian" last="Ball">Brian Ball</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Megerdichian, Christine" sort="Megerdichian, Christine" uniqKey="Megerdichian C" first="Christine" last="Megerdichian">Christine Megerdichian</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Okabe, Rachel" sort="Okabe, Rachel" uniqKey="Okabe R" first="Rachel" last="Okabe">Rachel Okabe</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Al Shahrour, Fatima" sort="Al Shahrour, Fatima" uniqKey="Al Shahrour F" first="Fatima" last="Al-Shahrour">Fatima Al-Shahrour</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Broad Institute, Cambridge, Massachusetts 02142, USA</nlm:aff></affiliation></author><author><name sortKey="Paktinat, Mahnaz" sort="Paktinat, Mahnaz" uniqKey="Paktinat M" first="Mahnaz" last="Paktinat">Mahnaz Paktinat</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Haydu, J Erika" sort="Haydu, J Erika" uniqKey="Haydu J" first="J. Erika" last="Haydu">J. Erika Haydu</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Housman, Elizabeth" sort="Housman, Elizabeth" uniqKey="Housman E" first="Elizabeth" last="Housman">Elizabeth Housman</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Lord, Allegra M" sort="Lord, Allegra M" uniqKey="Lord A" first="Allegra M." last="Lord">Allegra M. Lord</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Wernig, Gerlinde" sort="Wernig, Gerlinde" uniqKey="Wernig G" first="Gerlinde" last="Wernig">Gerlinde Wernig</name><affiliation><nlm:aff id="A5">Department of Pathology, Stanford University, California 94305, USA</nlm:aff></affiliation></author><author><name sortKey="Kharas, Michael G" sort="Kharas, Michael G" uniqKey="Kharas M" first="Michael G." last="Kharas">Michael G. Kharas</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Mercher, Thomas" sort="Mercher, Thomas" uniqKey="Mercher T" first="Thomas" last="Mercher">Thomas Mercher</name><affiliation><nlm:aff id="A6">INSERM U985, Université Paris Descartes, Hôpital Necker, 75015 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Kutok, Jeffery L" sort="Kutok, Jeffery L" uniqKey="Kutok J" first="Jeffery L." last="Kutok">Jeffery L. Kutok</name><affiliation><nlm:aff id="A7">Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation></author><author><name sortKey="Gilliland, D Gary" sort="Gilliland, D Gary" uniqKey="Gilliland D" first="D. Gary" last="Gilliland">D. Gary Gilliland</name><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A8">Merck & Co., North Wales, Pennsylvania 19454, USA</nlm:aff></affiliation></author><author><name sortKey="Ebert, Benjamin L" sort="Ebert, Benjamin L" uniqKey="Ebert B" first="Benjamin L." last="Ebert">Benjamin L. Ebert</name><affiliation><nlm:aff id="A1">Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A2">Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</nlm:aff></affiliation><affiliation><nlm:aff id="A3">Broad Institute, Cambridge, Massachusetts 02142, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Cancer cell</title><idno type="ISSN">1535-6108</idno><idno type="eISSN">1878-3686</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S1"><title>SUMMARY</title><p id="P2">We report a <italic>Jak2V617F</italic> knock-in mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a significant selective competitive advantage over wild type HSCs. In contrast, myeloid progenitor populations are expanded and skewed towards the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to <italic>JAK2V617F</italic> positive MPN.</p></sec><sec id="S2"><title>SIGNIFICANCE</title><p id="P3">The <italic>JAK2V617F</italic> mutation is a promising candidate for molecularly targeted therapy in MPN. Early data from JAK2 inhibitor clinical trials have called into question the capacity of these compounds to alter the natural history of <italic>JAK2V617F</italic> mediated MPN. Determining the effect of JAK2 inhibitors on the disease-initiating population requires a model in which the <italic>JAK2V617F</italic> allele is expressed at physiological levels in hematopoietic stem and progenitor cells, as it is in humans. Our model demonstrates that <italic>JAK2V617F</italic> causes expansion of erythroid progenitors but that only the HSC compartment can initiate disease in a transplanted mouse. We further demonstrate that the HSC compartment, the definitive target for curative therapy of <italic>JAK2V617F</italic> mediated MPN, is resistant to treatment with a JAK2 inhibitor.</p></sec></div></front></TEI><pmc article-type="research-article" xml:lang="EN"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101130617</journal-id><journal-id journal-id-type="pubmed-jr-id">29778</journal-id><journal-id journal-id-type="nlm-ta">Cancer Cell</journal-id><journal-title>Cancer cell</journal-title><issn pub-type="ppub">1535-6108</issn><issn pub-type="epub">1878-3686</issn></journal-meta><article-meta><article-id pub-id-type="pmid">20541703</article-id><article-id pub-id-type="pmc">2909585</article-id><article-id pub-id-type="doi">10.1016/j.ccr.2010.05.015</article-id><article-id pub-id-type="manuscript">NIHMS211336</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Physiological <italic>Jak2V617F</italic> expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Mullally</surname><given-names>Ann</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="author-notes" rid="FN1">9</xref></contrib><contrib contrib-type="author"><name><surname>Lane</surname><given-names>Steven W.</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A4">4</xref><xref ref-type="author-notes" rid="FN1">9</xref></contrib><contrib contrib-type="author"><name><surname>Ball</surname><given-names>Brian</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Megerdichian</surname><given-names>Christine</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Okabe</surname><given-names>Rachel</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Al-Shahrour</surname><given-names>Fatima</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Paktinat</surname><given-names>Mahnaz</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Haydu</surname><given-names>J. Erika</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Housman</surname><given-names>Elizabeth</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Lord</surname><given-names>Allegra M.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Wernig</surname><given-names>Gerlinde</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Kharas</surname><given-names>Michael G.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Mercher</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Kutok</surname><given-names>Jeffery L.</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Gilliland</surname><given-names>D. Gary</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Ebert</surname><given-names>Benjamin L.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref></contrib></contrib-group><aff id="A1"><label>1</label>Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA</aff><aff id="A2"><label>2</label>Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</aff><aff id="A3"><label>3</label>Broad Institute, Cambridge, Massachusetts 02142, USA</aff><aff id="A4"><label>4</label>University of Queensland, Brisbane, Australia</aff><aff id="A5"><label>5</label>Department of Pathology, Stanford University, California 94305, USA</aff><aff id="A6"><label>6</label>INSERM U985, Université Paris Descartes, Hôpital Necker, 75015 Paris, France</aff><aff id="A7"><label>7</label>Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA</aff><aff id="A8"><label>8</label>Merck & Co., North Wales, Pennsylvania 19454, USA</aff><author-notes><corresp id="cor1"><bold>Correspondence</bold>: <email>bebert@partners.org</email>, Phone: (617) 355-9091, Fax: (617) 355-9193, 1 Blackfan Circle, Karp Building 5.210, Boston, MA 02115</corresp><fn id="FN1" fn-type="equal"><label>9</label><p id="P1">These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>22</day><month>6</month><year>2010</year></pub-date><pub-date pub-type="ppub"><day>15</day><month>6</month><year>2010</year></pub-date><pub-date pub-type="pmc-release"><day>15</day><month>6</month><year>2011</year></pub-date><volume>17</volume><issue>6</issue><fpage>584</fpage><lpage>596</lpage><permissions><copyright-statement>© 2010 Elsevier Inc. All rights reserved.</copyright-statement><copyright-year>2010</copyright-year></permissions><abstract><sec id="S1"><title>SUMMARY</title><p id="P2">We report a <italic>Jak2V617F</italic> knock-in mouse myeloproliferative neoplasm (MPN) model resembling human polycythemia vera (PV). The MPN is serially transplantable and we demonstrate that the hematopoietic stem cell (HSC) compartment has the unique capacity for disease initiation but does not have a significant selective competitive advantage over wild type HSCs. In contrast, myeloid progenitor populations are expanded and skewed towards the erythroid lineage, but cannot transplant the disease. Treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. These findings provide insights into the consequences of JAK2 activation on HSC differentiation and function and have the potential to inform therapeutic approaches to <italic>JAK2V617F</italic> positive MPN.</p></sec><sec id="S2"><title>SIGNIFICANCE</title><p id="P3">The <italic>JAK2V617F</italic> mutation is a promising candidate for molecularly targeted therapy in MPN. Early data from JAK2 inhibitor clinical trials have called into question the capacity of these compounds to alter the natural history of <italic>JAK2V617F</italic> mediated MPN. Determining the effect of JAK2 inhibitors on the disease-initiating population requires a model in which the <italic>JAK2V617F</italic> allele is expressed at physiological levels in hematopoietic stem and progenitor cells, as it is in humans. Our model demonstrates that <italic>JAK2V617F</italic> causes expansion of erythroid progenitors but that only the HSC compartment can initiate disease in a transplanted mouse. We further demonstrate that the HSC compartment, the definitive target for curative therapy of <italic>JAK2V617F</italic> mediated MPN, is resistant to treatment with a JAK2 inhibitor.</p></sec></abstract><contract-num rid="HL1">R01 HL082945-04
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