Heritable GATA2 Mutations Associated with Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia
Identifieur interne : 004706 ( Pmc/Curation ); précédent : 004705; suivant : 004707Heritable GATA2 Mutations Associated with Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia
Auteurs : Christopher N. Hahn [Australie] ; Chan-Eng Chong [Australie] ; Catherine L. Carmichael [Australie] ; Ella J. Wilkins [Australie] ; Peter J. Brautigan [Australie] ; Xiao-Chun Li [Australie] ; Milena Babic [Australie] ; Ming Lin [Australie] ; Amandine Carmagnac [Australie] ; Young K. Lee [Australie] ; Chung H. Kok [Australie] ; Lucia Gagliardi [Australie] ; Kathryn L. Friend [Australie] ; Paul G. Ekert [Australie] ; Carolyn M. Butcher [Australie] ; Anna L. Brown [Australie] ; Ian D. Lewis [Australie] ; L. Bik To [Australie] ; Andrew E. Timms [États-Unis] ; Jan Storek [Canada] ; Sarah Moore [Australie] ; Meryl Altree [Australie] ; Robert Escher [Australie] ; Peter G. Bardy [Australie] ; Graeme K. Suthers [Australie] ; Richard J. D Ndrea [Australie] ; Marshall S. Horwitz [États-Unis] ; Hamish S. Scott [Australie]Source :
- Nature genetics [ 1061-4036 ] ; 2011.
Abstract
We report the discovery of the
Url:
DOI: 10.1038/ng.913
PubMed: 21892162
PubMed Central: 3184204
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Hahn</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Chong, Chan Eng" sort="Chong, Chan Eng" uniqKey="Chong C" first="Chan-Eng" last="Chong">Chan-Eng Chong</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Carmichael, Catherine L" sort="Carmichael, Catherine L" uniqKey="Carmichael C" first="Catherine L." last="Carmichael">Catherine L. Carmichael</name><affiliation wicri:level="1"><nlm:aff id="A3">Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic</wicri:regionArea></affiliation></author><author><name sortKey="Wilkins, Ella J" sort="Wilkins, Ella J" uniqKey="Wilkins E" first="Ella J." last="Wilkins">Ella J. 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Lee</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Kok, Chung H" sort="Kok, Chung H" uniqKey="Kok C" first="Chung H." last="Kok">Chung H. Kok</name><affiliation wicri:level="1"><nlm:aff id="A4">Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Gagliardi, Lucia" sort="Gagliardi, Lucia" uniqKey="Gagliardi L" first="Lucia" last="Gagliardi">Lucia Gagliardi</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Friend, Kathryn L" sort="Friend, Kathryn L" uniqKey="Friend K" first="Kathryn L." last="Friend">Kathryn L. Friend</name><affiliation wicri:level="1"><nlm:aff id="A6">Department of Paediatric and Reproductive Genetics, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Paediatric and Reproductive Genetics, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Ekert, Paul G" sort="Ekert, Paul G" uniqKey="Ekert P" first="Paul G." last="Ekert">Paul G. Ekert</name><affiliation wicri:level="1"><nlm:aff id="A7">Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic</wicri:regionArea></affiliation></author><author><name sortKey="Butcher, Carolyn M" sort="Butcher, Carolyn M" uniqKey="Butcher C" first="Carolyn M." last="Butcher">Carolyn M. Butcher</name><affiliation wicri:level="1"><nlm:aff id="A4">Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Brown, Anna L" sort="Brown, Anna L" uniqKey="Brown A" first="Anna L." last="Brown">Anna L. Brown</name><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Lewis, Ian D" sort="Lewis, Ian D" uniqKey="Lewis I" first="Ian D." last="Lewis">Ian D. Lewis</name><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="To, L Bik" sort="To, L Bik" uniqKey="To L" first="L. Bik" last="To">L. Bik To</name><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Timms, Andrew E" sort="Timms, Andrew E" uniqKey="Timms A" first="Andrew E." last="Timms">Andrew E. Timms</name><affiliation wicri:level="1"><nlm:aff id="A8">Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, University of Washington School of Medicine, Seattle, WA</wicri:regionArea></affiliation></author><author><name sortKey="Storek, Jan" sort="Storek, Jan" uniqKey="Storek J" first="Jan" last="Storek">Jan Storek</name><affiliation wicri:level="1"><nlm:aff id="A9">Department of Medicine, University of Calgary, Calgary, Alberta, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, University of Calgary, Calgary, Alberta</wicri:regionArea></affiliation></author><author><name sortKey="Moore, Sarah" sort="Moore, Sarah" uniqKey="Moore S" first="Sarah" last="Moore">Sarah Moore</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Altree, Meryl" sort="Altree, Meryl" uniqKey="Altree M" first="Meryl" last="Altree">Meryl Altree</name><affiliation wicri:level="1"><nlm:aff id="A10">SA Clinical Genetics Service, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>SA Clinical Genetics Service, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Escher, Robert" sort="Escher, Robert" uniqKey="Escher R" first="Robert" last="Escher">Robert Escher</name><affiliation wicri:level="1"><nlm:aff id="A3">Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic</wicri:regionArea></affiliation></author><author><name sortKey="Bardy, Peter G" sort="Bardy, Peter G" uniqKey="Bardy P" first="Peter G." last="Bardy">Peter G. Bardy</name><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Suthers, Graeme K" sort="Suthers, Graeme K" uniqKey="Suthers G" first="Graeme K." last="Suthers">Graeme K. Suthers</name><affiliation wicri:level="1"><nlm:aff id="A10">SA Clinical Genetics Service, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>SA Clinical Genetics Service, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A11">Department of Paediatrics, University of Adelaide, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Paediatrics, University of Adelaide, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="D Ndrea, Richard J" sort="D Ndrea, Richard J" uniqKey="D Ndrea R" first="Richard J." last="D Ndrea">Richard J. D Ndrea</name><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A4">Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Horwitz, Marshall S" sort="Horwitz, Marshall S" uniqKey="Horwitz M" first="Marshall S." last="Horwitz">Marshall S. Horwitz</name><affiliation wicri:level="1"><nlm:aff id="A8">Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, University of Washington School of Medicine, Seattle, WA</wicri:regionArea></affiliation></author><author><name sortKey="Scott, Hamish S" sort="Scott, Hamish S" uniqKey="Scott H" first="Hamish S." last="Scott">Hamish S. Scott</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A3">Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A12">School of Molecular and Biomedical Science, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Molecular and Biomedical Science, University of Adelaide, SA</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21892162</idno><idno type="pmc">3184204</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184204</idno><idno type="RBID">PMC:3184204</idno><idno type="doi">10.1038/ng.913</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">004707</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">004707</idno><idno type="wicri:Area/Pmc/Curation">004706</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">004706</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Heritable <italic>GATA2</italic> Mutations Associated with Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia</title><author><name sortKey="Hahn, Christopher N" sort="Hahn, Christopher N" uniqKey="Hahn C" first="Christopher N." last="Hahn">Christopher N. Hahn</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Chong, Chan Eng" sort="Chong, Chan Eng" uniqKey="Chong C" first="Chan-Eng" last="Chong">Chan-Eng Chong</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Carmichael, Catherine L" sort="Carmichael, Catherine L" uniqKey="Carmichael C" first="Catherine L." last="Carmichael">Catherine L. Carmichael</name><affiliation wicri:level="1"><nlm:aff id="A3">Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic</wicri:regionArea></affiliation></author><author><name sortKey="Wilkins, Ella J" sort="Wilkins, Ella J" uniqKey="Wilkins E" first="Ella J." last="Wilkins">Ella J. Wilkins</name><affiliation wicri:level="1"><nlm:aff id="A3">Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic</wicri:regionArea></affiliation></author><author><name sortKey="Brautigan, Peter J" sort="Brautigan, Peter J" uniqKey="Brautigan P" first="Peter J." last="Brautigan">Peter J. Brautigan</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Li, Xiao Chun" sort="Li, Xiao Chun" uniqKey="Li X" first="Xiao-Chun" last="Li">Xiao-Chun Li</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Babic, Milena" sort="Babic, Milena" uniqKey="Babic M" first="Milena" last="Babic">Milena Babic</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Lin, Ming" sort="Lin, Ming" uniqKey="Lin M" first="Ming" last="Lin">Ming Lin</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Carmagnac, Amandine" sort="Carmagnac, Amandine" uniqKey="Carmagnac A" first="Amandine" last="Carmagnac">Amandine Carmagnac</name><affiliation wicri:level="1"><nlm:aff id="A3">Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic</wicri:regionArea></affiliation></author><author><name sortKey="Lee, Young K" sort="Lee, Young K" uniqKey="Lee Y" first="Young K." last="Lee">Young K. Lee</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Kok, Chung H" sort="Kok, Chung H" uniqKey="Kok C" first="Chung H." last="Kok">Chung H. Kok</name><affiliation wicri:level="1"><nlm:aff id="A4">Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Gagliardi, Lucia" sort="Gagliardi, Lucia" uniqKey="Gagliardi L" first="Lucia" last="Gagliardi">Lucia Gagliardi</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Friend, Kathryn L" sort="Friend, Kathryn L" uniqKey="Friend K" first="Kathryn L." last="Friend">Kathryn L. Friend</name><affiliation wicri:level="1"><nlm:aff id="A6">Department of Paediatric and Reproductive Genetics, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Paediatric and Reproductive Genetics, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Ekert, Paul G" sort="Ekert, Paul G" uniqKey="Ekert P" first="Paul G." last="Ekert">Paul G. Ekert</name><affiliation wicri:level="1"><nlm:aff id="A7">Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic</wicri:regionArea></affiliation></author><author><name sortKey="Butcher, Carolyn M" sort="Butcher, Carolyn M" uniqKey="Butcher C" first="Carolyn M." last="Butcher">Carolyn M. Butcher</name><affiliation wicri:level="1"><nlm:aff id="A4">Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Brown, Anna L" sort="Brown, Anna L" uniqKey="Brown A" first="Anna L." last="Brown">Anna L. Brown</name><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Lewis, Ian D" sort="Lewis, Ian D" uniqKey="Lewis I" first="Ian D." last="Lewis">Ian D. Lewis</name><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="To, L Bik" sort="To, L Bik" uniqKey="To L" first="L. Bik" last="To">L. Bik To</name><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Timms, Andrew E" sort="Timms, Andrew E" uniqKey="Timms A" first="Andrew E." last="Timms">Andrew E. Timms</name><affiliation wicri:level="1"><nlm:aff id="A8">Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, University of Washington School of Medicine, Seattle, WA</wicri:regionArea></affiliation></author><author><name sortKey="Storek, Jan" sort="Storek, Jan" uniqKey="Storek J" first="Jan" last="Storek">Jan Storek</name><affiliation wicri:level="1"><nlm:aff id="A9">Department of Medicine, University of Calgary, Calgary, Alberta, Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Medicine, University of Calgary, Calgary, Alberta</wicri:regionArea></affiliation></author><author><name sortKey="Moore, Sarah" sort="Moore, Sarah" uniqKey="Moore S" first="Sarah" last="Moore">Sarah Moore</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Altree, Meryl" sort="Altree, Meryl" uniqKey="Altree M" first="Meryl" last="Altree">Meryl Altree</name><affiliation wicri:level="1"><nlm:aff id="A10">SA Clinical Genetics Service, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>SA Clinical Genetics Service, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Escher, Robert" sort="Escher, Robert" uniqKey="Escher R" first="Robert" last="Escher">Robert Escher</name><affiliation wicri:level="1"><nlm:aff id="A3">Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic</wicri:regionArea></affiliation></author><author><name sortKey="Bardy, Peter G" sort="Bardy, Peter G" uniqKey="Bardy P" first="Peter G." last="Bardy">Peter G. Bardy</name><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Suthers, Graeme K" sort="Suthers, Graeme K" uniqKey="Suthers G" first="Graeme K." last="Suthers">Graeme K. Suthers</name><affiliation wicri:level="1"><nlm:aff id="A10">SA Clinical Genetics Service, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>SA Clinical Genetics Service, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A11">Department of Paediatrics, University of Adelaide, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Paediatrics, University of Adelaide, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="D Ndrea, Richard J" sort="D Ndrea, Richard J" uniqKey="D Ndrea R" first="Richard J." last="D Ndrea">Richard J. D Ndrea</name><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A4">Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A5">Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation></author><author><name sortKey="Horwitz, Marshall S" sort="Horwitz, Marshall S" uniqKey="Horwitz M" first="Marshall S." last="Horwitz">Marshall S. Horwitz</name><affiliation wicri:level="1"><nlm:aff id="A8">Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, University of Washington School of Medicine, Seattle, WA</wicri:regionArea></affiliation></author><author><name sortKey="Scott, Hamish S" sort="Scott, Hamish S" uniqKey="Scott H" first="Hamish S." last="Scott">Hamish S. Scott</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Medicine, University of Adelaide, SA</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A3">Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="A12">School of Molecular and Biomedical Science, University of Adelaide, SA, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Molecular and Biomedical Science, University of Adelaide, SA</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature genetics</title><idno type="ISSN">1061-4036</idno><idno type="eISSN">1546-1718</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">We report the discovery of the <italic>GATA2</italic> gene as a new myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) predisposition gene. We found the same, novel heterozygous c.1061C>T (p.Thr354Met) missense mutation in the <italic>GATA2</italic> transcription factor gene segregating with the multigenerational transmission of MDS/AML in three families, and a <italic>GATA2</italic> c.1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS/AML family. The mutations reside within the second zinc finger of GATA2 which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutants on transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counselling, selection of related bone marrow transplant donors, and development of therapies.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Vardiman, Jw" uniqKey="Vardiman J">JW Vardiman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barzi, A" uniqKey="Barzi A">A Barzi</name></author><author><name sortKey="Sekeres, Ma" uniqKey="Sekeres M">MA Sekeres</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Owen, C" uniqKey="Owen C">C Owen</name></author><author><name sortKey="Barnett, M" uniqKey="Barnett M">M Barnett</name></author><author><name sortKey="Fitzgibbon, J" uniqKey="Fitzgibbon J">J Fitzgibbon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, P" uniqKey="Zhang P">P 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<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9216904</journal-id><journal-id journal-id-type="pubmed-jr-id">2419</journal-id><journal-id journal-id-type="nlm-ta">Nat Genet</journal-id><journal-id journal-id-type="iso-abbrev">Nat. Genet.</journal-id><journal-title-group><journal-title>Nature genetics</journal-title></journal-title-group><issn pub-type="ppub">1061-4036</issn><issn pub-type="epub">1546-1718</issn></journal-meta><article-meta><article-id pub-id-type="pmid">21892162</article-id><article-id pub-id-type="pmc">3184204</article-id><article-id pub-id-type="doi">10.1038/ng.913</article-id><article-id pub-id-type="manuscript">NIHMS315105</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Heritable <italic>GATA2</italic> Mutations Associated with Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Hahn</surname><given-names>Christopher N.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Chong</surname><given-names>Chan-Eng</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="aff" rid="A2">2</xref><xref rid="FN4" ref-type="author-notes">15</xref></contrib><contrib contrib-type="author"><name><surname>Carmichael</surname><given-names>Catherine L.</given-names></name><xref ref-type="aff" rid="A3">3</xref><xref rid="FN4" ref-type="author-notes">15</xref></contrib><contrib contrib-type="author"><name><surname>Wilkins</surname><given-names>Ella J.</given-names></name><xref ref-type="aff" rid="A3">3</xref><xref rid="FN2" ref-type="author-notes">13</xref></contrib><contrib contrib-type="author"><name><surname>Brautigan</surname><given-names>Peter J.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Xiao-Chun</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Babic</surname><given-names>Milena</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Lin</surname><given-names>Ming</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Carmagnac</surname><given-names>Amandine</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Young K.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kok</surname><given-names>Chung H.</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Gagliardi</surname><given-names>Lucia</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Friend</surname><given-names>Kathryn L.</given-names></name><xref ref-type="aff" rid="A6">6</xref></contrib><contrib contrib-type="author"><name><surname>Ekert</surname><given-names>Paul G.</given-names></name><xref ref-type="aff" rid="A7">7</xref></contrib><contrib contrib-type="author"><name><surname>Butcher</surname><given-names>Carolyn M.</given-names></name><xref ref-type="aff" rid="A4">4</xref><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Brown</surname><given-names>Anna L.</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Lewis</surname><given-names>Ian D.</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>To</surname><given-names>L. Bik</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Timms</surname><given-names>Andrew E.</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Storek</surname><given-names>Jan</given-names></name><xref ref-type="aff" rid="A9">9</xref></contrib><contrib contrib-type="author"><name><surname>Moore</surname><given-names>Sarah</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Altree</surname><given-names>Meryl</given-names></name><xref ref-type="aff" rid="A10">10</xref></contrib><contrib contrib-type="author"><name><surname>Escher</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="A3">3</xref><xref rid="FN3" ref-type="author-notes">14</xref></contrib><contrib contrib-type="author"><name><surname>Bardy</surname><given-names>Peter G.</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Suthers</surname><given-names>Graeme K.</given-names></name><xref ref-type="aff" rid="A10">10</xref><xref ref-type="aff" rid="A11">11</xref></contrib><contrib contrib-type="author"><name><surname>D’Andrea</surname><given-names>Richard J.</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A4">4</xref><xref ref-type="aff" rid="A5">5</xref><xref rid="FN5" ref-type="author-notes">16</xref></contrib><contrib contrib-type="author"><name><surname>Horwitz</surname><given-names>Marshall S.</given-names></name><xref ref-type="aff" rid="A8">8</xref></contrib><contrib contrib-type="author"><name><surname>Scott</surname><given-names>Hamish S.</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><xref ref-type="aff" rid="A12">12</xref><xref rid="FN5" ref-type="author-notes">16</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</aff><aff id="A2"><label>2</label>School of Medicine, University of Adelaide, SA, Australia</aff><aff id="A3"><label>3</label>Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia</aff><aff id="A4"><label>4</label>Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, SA, Australia</aff><aff id="A5"><label>5</label>Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia</aff><aff id="A6"><label>6</label>Department of Paediatric and Reproductive Genetics, SA Pathology, Adelaide, SA, Australia</aff><aff id="A7"><label>7</label>Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Vic, Australia</aff><aff id="A8"><label>8</label>Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA</aff><aff id="A9"><label>9</label>Department of Medicine, University of Calgary, Calgary, Alberta, Canada</aff><aff id="A10"><label>10</label>SA Clinical Genetics Service, SA Pathology, Adelaide, SA, Australia</aff><aff id="A11"><label>11</label>Department of Paediatrics, University of Adelaide, Adelaide, SA, Australia</aff><aff id="A12"><label>12</label>School of Molecular and Biomedical Science, University of Adelaide, SA, Australia</aff><author-notes><corresp id="FN1">Correspondence should be addressed to H.S.S. (<email>hamish.scott@health.sa.gov.au</email>)</corresp><fn id="FN2" fn-type="present-address"><label>13</label><p>Present Address: Neurogenetics Laboratory, Howard Florey Institute, Parkville, VIC, Australia.</p></fn><fn id="FN3" fn-type="present-address"><label>14</label><p>Present Address: Medical Clinic, Regional Hospital Emmental, Burgdorf, Switzerland.</p></fn><fn id="FN4" fn-type="equal"><label>15</label><p>These authors contributed equally to this work.</p></fn><fn id="FN5"><label>16</label><p>These authors jointly supervised this work.</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>1</day><month>8</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>04</day><month>9</month><year>2011</year></pub-date><pub-date pub-type="collection"><month>10</month><year>2011</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>4</month><year>2012</year></pub-date><volume>43</volume><issue>10</issue><fpage>1012</fpage><lpage>1017</lpage><pmc-comment>elocation-id from pubmed: 10.1038/ng.913</pmc-comment>
<permissions><license><license-p>Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
<uri xlink:type="simple" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</uri></license-p></license></permissions><abstract><p id="P1">We report the discovery of the <italic>GATA2</italic> gene as a new myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) predisposition gene. We found the same, novel heterozygous c.1061C>T (p.Thr354Met) missense mutation in the <italic>GATA2</italic> transcription factor gene segregating with the multigenerational transmission of MDS/AML in three families, and a <italic>GATA2</italic> c.1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS/AML family. The mutations reside within the second zinc finger of GATA2 which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutants on transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counselling, selection of related bone marrow transplant donors, and development of therapies.</p></abstract></article-meta></front><floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>Identification of novel germline p.Thr354Met and p.Thr355del variants in the highly conserved zinc finger 2 domain of GATA2 that is associated with MDS-AML</title><p><bold>a.</bold> Pedigrees containing the p.Thr354Met and p.Thr355del variants. One family from Australia (Pedigree 1) and two from the USA (Pedigrees 2 and 3) display the p.Thr354Met variant segregating with MDS-AML, and one USA family (Pedigree 4) contains a p.Thr355del variant that segregates with MDS. The genotype of tested individuals is shown; T354, (Thr354/Thr354); T354M, (Thr354/Met354). <bold>b.</bold> Domain structure of GATA2 showing positions of mutations. The positions of the p.Thr354Met, p.Thr355del, AML-M5<sup><xref rid="R7" ref-type="bibr">7</xref></sup> (green) and CML BC<sup><xref rid="R6" ref-type="bibr">6</xref></sup> (black) mutations are shown with respect to zinc finger (ZF) 1 and 2, transactivation domain (TA) and nuclear localization signal (NLS). <bold>c.</bold> Zinc finger 2 (ZF2) domain of GATA2 and GATA3 contains mutations associated with leukemia and breast cancer. The primary sequence is that of human GATA2 with the two alternative residues in GATA3 ZF2 shown (light grey with black letters). The position of p.Thr354Met and p.Thr355del is highlighted along with mutations found in GATA2 in AML-M5<sup><xref rid="R7" ref-type="bibr">7</xref></sup> (green) and CML BC<sup><xref rid="R6" ref-type="bibr">6</xref></sup> (black), and in GATA3 in breast cancer (summarized in <sup><xref rid="R8" ref-type="bibr">8</xref></sup>) (mutated residues in the corresponding GATA3 ZF2; grey with white letters).</p></caption><graphic xlink:href="nihms315105f1"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>Subcellular localisation and DNA binding properties of GATA2 WT and mutants</title><p>HEK293 cells were transiently transfected with EV (pCMV-XL6 empty vector), WT, p.Thr354Met, p.Thr355del or p.Leu359Val and harvested after 24 h. <bold>a.</bold> Western blot analysis of GATA2 expression in nuclear lysates. Nuclear lysates were prepared and western blots performed, probing for GATA2. <bold>b.</bold> Cells were stained for GATA2 (red) and DAPI (blue). Scale bars, 10 μm. <bold>c.</bold> Electromobility shift assay (EMSA) of GATA2 WT and mutants. Nuclear lysates were prepared and bound to the TCRδ enhancer (contains GATA binding site) oligonucleotide in the absence or presence of 200-fold unlabeled competitor oligonucleotide (<bold>D</bold>, human TCRδ enhancer; <bold>C</bold>, GATA consensus; <bold>G</bold>, GM-CSF promoter). The probes were visualised using chemiluminescence (top panel). Note, GATA2 & NS relates to a band that contains both GATA2 and a non-specific (NS) protein. To visualise GATA2 alone, an EMSA-western blot was performed probing with polyclonal α-GATA2 antibody (bottom panel), showing the level of binding of GATA2 WT and mutants. A neutralizing α-GATA2 antibody in the far right lane removes GATA2, but not the non-specific binding protein (NS) (top panel), and the specificity of GATA2 is confirmed in the bottom panel.</p></caption><graphic xlink:href="nihms315105f2"></graphic></fig><fig id="F3" orientation="portrait" position="float"><label>Figure 3</label><caption><title>p.Thr354Met and p.Thr355del cause altered transactivation via target GATA2 response elements</title><p>p.Thr354Met and p.Thr355del act as a loss-of-function mutations on GATA2 target promoter and enhancer elements. HEK293 cells were cotransfected with 1) GATA2-responsive <italic>CD34</italic> (mut – <italic>CD34</italic> enhancer with GATA binding sites mutated<sup><xref rid="R31" ref-type="bibr">31</xref></sup>) (<bold>a</bold>) and <italic>RUNX1</italic> (<bold>b</bold>) enhancer elements linked to a LUC reporter, and 2) GATA2 (WT, p.Thr354Met, p.Thr355del or p.Leu359Val) expression constructs or pCMV6-XL6 empty vector (EV). Similarly, Cos-7 cells were cotransfected using <italic>LYL1</italic> promoter LUC as reporter (<bold>c</bold>). After 20 h, cells were harvested and luciferase assays performed and plotted as fold (mean ± s.e.m.) compared to EV control. Pairwise comparisons are shown (*p<0.05, n = 3). <bold>d.</bold> p.Thr354Met and p.Thr355del act as dominant negative mutations over WT GATA2. HEK293 cells were cotransfected with: 1) <italic>CD34</italic> enhancer-LUC reporter, and equivalent mole ratios of 2) WT to 3) p.Thr354Met or p.Thr355del. After 20 h, cells were harvested and luciferase assays performed. Pairwise comparisons are shown (*p<0.05; NS -not significant, n=3). <bold>e.</bold> p.Thr354Met has reduced ability to co-activate the <italic>CSF1R</italic> (<italic>M-CSF-R</italic>) promoter with PU.1. Cos-7 cells were cotransfected with 1) <italic>CSF1R</italic> promoter-LUC reporter, 2) PU.1 expression construct, and 3) WT, p.Thr354Met, p.Thr355del or p.Leu359Val expression constructs or EV. After 20 h, luciferase assays were performed and plotted as fold compared to EV. Pairwise comparisons are shown (*p<0.05, compared to WT plus PU.1; **p<0.05 compared to WT plus PU.1, but not significant when compared to p.Thr354Met or p.Thr355del plus PU.1, respectively). In all comparisons, a Student’s t-test was used.</p></caption><graphic xlink:href="nihms315105f3"></graphic></fig><fig id="F4" orientation="portrait" position="float"><label>Figure 4</label><caption><title>p.Thr354Met inhibits differentiation and apoptosis while allowing accumulation of cells in the presence of ATRA-induced differentiation</title><p>HL-60 cells carrying stably transduced 4HT-regulatable GATA2 (WT, p.Thr354Met, p.Thr355del and p.Leu359Val) or EV were treated with or without 30 nM 4HT for 24 h and then with or without 2 μM ATRA for 6 days. <bold>a–d.</bold> Differentiation of HL-60 cells into granulocytes. Differentiation was measured by FACS analysis for percentage of CD11b positive cells (mean ± s.e.m.) (see also <xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 7b</xref>). <bold>e–h.</bold> Cell numbers following differentiation. Cells were counted after 6 days (mean ± s.e.m.). <bold>i–m.</bold> Apoptosis following differentiation with ATRA. Cells were FACS analysed following staining with FITC anti-Annexin V and propidium iodide (PI). Annexin V<sup>+</sup>, PI<sup>−</sup> (black) or Annexin V<sup>+</sup>, PI<sup>+</sup> (white). Indicative FACS plots (<xref rid="SD1" ref-type="supplementary-material">Supplementary Fig. 7c</xref>). <bold>a,e,i.</bold> −4HT, −ATRA; <bold>b,f,j.</bold> +4HT, −ATRA; <bold>c,g,k.</bold> −4HT, +ATRA; <bold>d,h,m.</bold> +4HT, +ATRA.(*p<0.05; **p<0.01, compared to WT). In all comparisons, a Student’s t-test was used.</p></caption><graphic xlink:href="nihms315105f4"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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