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FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors

Identifieur interne : 000321 ( Main/Exploration ); précédent : 000320; suivant : 000322

FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors

Auteurs : Adam J. Mead [Royaume-Uni] ; Shabnam Kharazi [Suède] ; Deborah Atkinson [Royaume-Uni] ; Iain Macaulay [Royaume-Uni] ; Christian Pecquet [Belgique] ; Stephen Loughran [Royaume-Uni] ; Michael Lutteropp [Royaume-Uni] ; Petter Woll [Royaume-Uni] ; Onima Chowdhury [Royaume-Uni] ; Sidinh Luc [Royaume-Uni] ; Natalija Buza-Vidas [Royaume-Uni] ; Helen Ferry [Royaume-Uni] ; Sally-Ann Clark [Royaume-Uni] ; Nicolas Goardon [Royaume-Uni] ; Paresh Vyas [Royaume-Uni] ; Stefan N. Constantinescu [Belgique] ; Ewa Sitnicka [Suède] ; Claus Nerlov [Royaume-Uni] ; Sten Eirik W. Jacobsen [Royaume-Uni]

Source :

RBID : PMC:3701326

Abstract

Summary

Whether signals mediated via growth factor receptors (GFRs) might influence lineage fate in multipotent progenitors (MPPs) is unclear. We explored this issue in a mouse knockin model of gain-of-function Flt3-ITD mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. When expressed in MPPs, Flt3-ITD collaborated with Runx1 mutation to induce high-penetrance aggressive leukemias that were exclusively of the myeloid phenotype. Flt3-ITDs preferentially expanded MPPs with reduced lymphoid and increased myeloid transcriptional priming while compromising early B and T lymphopoiesis. Flt3-ITD-induced myeloid lineage bias involved upregulation of the transcription factor Pu.1, which is a direct target gene of Stat3, an aberrantly activated target of Flt3-ITDs, further establishing how lineage bias can be inflicted on MPPs through aberrant GFR signaling. Collectively, these findings provide new insights into how oncogenic mutations might subvert the normal process of lineage commitment and dictate the phenotype of resulting malignancies.


Url:
DOI: 10.1016/j.celrep.2013.04.031
PubMed: 23727242
PubMed Central: 3701326


Affiliations:


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<title xml:lang="en" level="a" type="main">FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors</title>
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<name sortKey="Pecquet, Christian" sort="Pecquet, Christian" uniqKey="Pecquet C" first="Christian" last="Pecquet">Christian Pecquet</name>
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<settlement type="city">Bruxelles</settlement>
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</placeName>
</affiliation>
<affiliation wicri:level="4">
<nlm:aff id="aff5">de Duve Institute, Université Catholique de Louvain, Brussels B1200, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
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<settlement type="city">Bruxelles</settlement>
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</placeName>
<orgName type="university">Université catholique de Louvain</orgName>
<placeName>
<settlement type="city">Louvain-la-Neuve</settlement>
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<region type="province" nuts="1">Province du Brabant wallon</region>
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<author>
<name sortKey="Loughran, Stephen" sort="Loughran, Stephen" uniqKey="Loughran S" first="Stephen" last="Loughran">Stephen Loughran</name>
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<nlm:aff id="aff1">Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
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<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
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<author>
<name sortKey="Lutteropp, Michael" sort="Lutteropp, Michael" uniqKey="Lutteropp M" first="Michael" last="Lutteropp">Michael Lutteropp</name>
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<nlm:aff id="aff1">Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
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<author>
<name sortKey="Woll, Petter" sort="Woll, Petter" uniqKey="Woll P" first="Petter" last="Woll">Petter Woll</name>
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<nlm:aff id="aff1">Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
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<settlement type="city">Oxford</settlement>
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</affiliation>
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<author>
<name sortKey="Chowdhury, Onima" sort="Chowdhury, Onima" uniqKey="Chowdhury O" first="Onima" last="Chowdhury">Onima Chowdhury</name>
<affiliation wicri:level="4">
<nlm:aff id="aff1">Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
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<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
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</placeName>
</affiliation>
</author>
<author>
<name sortKey="Luc, Sidinh" sort="Luc, Sidinh" uniqKey="Luc S" first="Sidinh" last="Luc">Sidinh Luc</name>
<affiliation wicri:level="4">
<nlm:aff id="aff1">Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
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<orgName type="university">Université d'Oxford</orgName>
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<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
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</author>
<author>
<name sortKey="Buza Vidas, Natalija" sort="Buza Vidas, Natalija" uniqKey="Buza Vidas N" first="Natalija" last="Buza-Vidas">Natalija Buza-Vidas</name>
<affiliation wicri:level="4">
<nlm:aff id="aff1">Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
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<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Ferry, Helen" sort="Ferry, Helen" uniqKey="Ferry H" first="Helen" last="Ferry">Helen Ferry</name>
<affiliation wicri:level="4">
<nlm:aff id="aff1">Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
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<orgName type="university">Université d'Oxford</orgName>
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<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
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</author>
<author>
<name sortKey="Clark, Sally Ann" sort="Clark, Sally Ann" uniqKey="Clark S" first="Sally-Ann" last="Clark">Sally-Ann Clark</name>
<affiliation wicri:level="4">
<nlm:aff id="aff1">Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
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<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Goardon, Nicolas" sort="Goardon, Nicolas" uniqKey="Goardon N" first="Nicolas" last="Goardon">Nicolas Goardon</name>
<affiliation wicri:level="4">
<nlm:aff id="aff2">MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Vyas, Paresh" sort="Vyas, Paresh" uniqKey="Vyas P" first="Paresh" last="Vyas">Paresh Vyas</name>
<affiliation wicri:level="4">
<nlm:aff id="aff2">MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Constantinescu, Stefan N" sort="Constantinescu, Stefan N" uniqKey="Constantinescu S" first="Stefan N." last="Constantinescu">Stefan N. Constantinescu</name>
<affiliation wicri:level="1">
<nlm:aff id="aff4">Ludwig Institute for Cancer Research, Brussels B1200, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>Ludwig Institute for Cancer Research, Brussels B1200</wicri:regionArea>
<placeName>
<settlement type="city">Bruxelles</settlement>
<region nuts="2">Région de Bruxelles-Capitale</region>
</placeName>
</affiliation>
<affiliation wicri:level="4">
<nlm:aff id="aff5">de Duve Institute, Université Catholique de Louvain, Brussels B1200, Belgium</nlm:aff>
<country xml:lang="fr">Belgique</country>
<wicri:regionArea>de Duve Institute, Université Catholique de Louvain, Brussels B1200</wicri:regionArea>
<placeName>
<settlement type="city">Bruxelles</settlement>
<region nuts="2">Région de Bruxelles-Capitale</region>
</placeName>
<orgName type="university">Université catholique de Louvain</orgName>
<placeName>
<settlement type="city">Louvain-la-Neuve</settlement>
<region type="region" nuts="1">Région wallonne</region>
<region type="province" nuts="1">Province du Brabant wallon</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Sitnicka, Ewa" sort="Sitnicka, Ewa" uniqKey="Sitnicka E" first="Ewa" last="Sitnicka">Ewa Sitnicka</name>
<affiliation wicri:level="1">
<nlm:aff id="aff3">Hematopoietic Stem Cell Laboratory, Lund Stem Cell Center, Lund University, Lund 22184, Sweden</nlm:aff>
<country xml:lang="fr">Suède</country>
<wicri:regionArea>Hematopoietic Stem Cell Laboratory, Lund Stem Cell Center, Lund University, Lund 22184</wicri:regionArea>
<wicri:noRegion>Lund 22184</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Nerlov, Claus" sort="Nerlov, Claus" uniqKey="Nerlov C" first="Claus" last="Nerlov">Claus Nerlov</name>
<affiliation wicri:level="4">
<nlm:aff id="aff2">MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
<affiliation wicri:level="4">
<nlm:aff id="aff6">Institute for Stem Cell Research, MRC Centre for Regenerative Medicine, University of Edinburgh, King’s Buildings, West Mains Road, Edinburgh EH93JQ, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Institute for Stem Cell Research, MRC Centre for Regenerative Medicine, University of Edinburgh, King’s Buildings, West Mains Road, Edinburgh EH93JQ</wicri:regionArea>
<orgName type="university">Université d'Édimbourg</orgName>
<placeName>
<settlement type="city">Édimbourg</settlement>
<region type="country">Écosse</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Jacobsen, Sten Eirik W" sort="Jacobsen, Sten Eirik W" uniqKey="Jacobsen S" first="Sten Eirik W." last="Jacobsen">Sten Eirik W. Jacobsen</name>
<affiliation wicri:level="4">
<nlm:aff id="aff1">Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Haematopoietic Stem Cell Biology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
<affiliation wicri:level="4">
<nlm:aff id="aff2">MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName>
<settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Cell Reports</title>
<idno type="eISSN">2211-1247</idno>
<imprint>
<date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<title>Summary</title>
<p>Whether signals mediated via growth factor receptors (GFRs) might influence lineage fate in multipotent progenitors (MPPs) is unclear. We explored this issue in a mouse knockin model of gain-of-function
<italic>Flt3-ITD</italic>
mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. When expressed in MPPs, Flt3-ITD collaborated with
<italic>Runx1</italic>
mutation to induce high-penetrance aggressive leukemias that were exclusively of the myeloid phenotype. Flt3-ITDs preferentially expanded MPPs with reduced lymphoid and increased myeloid transcriptional priming while compromising early B and T lymphopoiesis. Flt3-ITD-induced myeloid lineage bias involved upregulation of the transcription factor
<italic>Pu.1</italic>
, which is a direct target gene of Stat3, an aberrantly activated target of Flt3-ITDs, further establishing how lineage bias can be inflicted on MPPs through aberrant GFR signaling. Collectively, these findings provide new insights into how oncogenic mutations might subvert the normal process of lineage commitment and dictate the phenotype of resulting malignancies.</p>
</div>
</front>
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<li>Écosse</li>
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<li>Bruxelles</li>
<li>Louvain-la-Neuve</li>
<li>Oxford</li>
<li>Édimbourg</li>
</settlement>
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<li>Université catholique de Louvain</li>
<li>Université d'Oxford</li>
<li>Université d'Édimbourg</li>
</orgName>
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<name sortKey="Mead, Adam J" sort="Mead, Adam J" uniqKey="Mead A" first="Adam J." last="Mead">Adam J. Mead</name>
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<name sortKey="Buza Vidas, Natalija" sort="Buza Vidas, Natalija" uniqKey="Buza Vidas N" first="Natalija" last="Buza-Vidas">Natalija Buza-Vidas</name>
<name sortKey="Chowdhury, Onima" sort="Chowdhury, Onima" uniqKey="Chowdhury O" first="Onima" last="Chowdhury">Onima Chowdhury</name>
<name sortKey="Clark, Sally Ann" sort="Clark, Sally Ann" uniqKey="Clark S" first="Sally-Ann" last="Clark">Sally-Ann Clark</name>
<name sortKey="Ferry, Helen" sort="Ferry, Helen" uniqKey="Ferry H" first="Helen" last="Ferry">Helen Ferry</name>
<name sortKey="Goardon, Nicolas" sort="Goardon, Nicolas" uniqKey="Goardon N" first="Nicolas" last="Goardon">Nicolas Goardon</name>
<name sortKey="Jacobsen, Sten Eirik W" sort="Jacobsen, Sten Eirik W" uniqKey="Jacobsen S" first="Sten Eirik W." last="Jacobsen">Sten Eirik W. Jacobsen</name>
<name sortKey="Jacobsen, Sten Eirik W" sort="Jacobsen, Sten Eirik W" uniqKey="Jacobsen S" first="Sten Eirik W." last="Jacobsen">Sten Eirik W. Jacobsen</name>
<name sortKey="Loughran, Stephen" sort="Loughran, Stephen" uniqKey="Loughran S" first="Stephen" last="Loughran">Stephen Loughran</name>
<name sortKey="Luc, Sidinh" sort="Luc, Sidinh" uniqKey="Luc S" first="Sidinh" last="Luc">Sidinh Luc</name>
<name sortKey="Lutteropp, Michael" sort="Lutteropp, Michael" uniqKey="Lutteropp M" first="Michael" last="Lutteropp">Michael Lutteropp</name>
<name sortKey="Lutteropp, Michael" sort="Lutteropp, Michael" uniqKey="Lutteropp M" first="Michael" last="Lutteropp">Michael Lutteropp</name>
<name sortKey="Macaulay, Iain" sort="Macaulay, Iain" uniqKey="Macaulay I" first="Iain" last="Macaulay">Iain Macaulay</name>
<name sortKey="Macaulay, Iain" sort="Macaulay, Iain" uniqKey="Macaulay I" first="Iain" last="Macaulay">Iain Macaulay</name>
<name sortKey="Nerlov, Claus" sort="Nerlov, Claus" uniqKey="Nerlov C" first="Claus" last="Nerlov">Claus Nerlov</name>
<name sortKey="Nerlov, Claus" sort="Nerlov, Claus" uniqKey="Nerlov C" first="Claus" last="Nerlov">Claus Nerlov</name>
<name sortKey="Vyas, Paresh" sort="Vyas, Paresh" uniqKey="Vyas P" first="Paresh" last="Vyas">Paresh Vyas</name>
<name sortKey="Woll, Petter" sort="Woll, Petter" uniqKey="Woll P" first="Petter" last="Woll">Petter Woll</name>
</country>
<country name="Suède">
<noRegion>
<name sortKey="Kharazi, Shabnam" sort="Kharazi, Shabnam" uniqKey="Kharazi S" first="Shabnam" last="Kharazi">Shabnam Kharazi</name>
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<name sortKey="Sitnicka, Ewa" sort="Sitnicka, Ewa" uniqKey="Sitnicka E" first="Ewa" last="Sitnicka">Ewa Sitnicka</name>
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<country name="Belgique">
<region name="Région de Bruxelles-Capitale">
<name sortKey="Pecquet, Christian" sort="Pecquet, Christian" uniqKey="Pecquet C" first="Christian" last="Pecquet">Christian Pecquet</name>
</region>
<name sortKey="Constantinescu, Stefan N" sort="Constantinescu, Stefan N" uniqKey="Constantinescu S" first="Stefan N." last="Constantinescu">Stefan N. Constantinescu</name>
<name sortKey="Constantinescu, Stefan N" sort="Constantinescu, Stefan N" uniqKey="Constantinescu S" first="Stefan N." last="Constantinescu">Stefan N. Constantinescu</name>
<name sortKey="Pecquet, Christian" sort="Pecquet, Christian" uniqKey="Pecquet C" first="Christian" last="Pecquet">Christian Pecquet</name>
</country>
</tree>
</affiliations>
</record>

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