Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia
Identifieur interne : 003A88 ( Ncbi/Curation ); précédent : 003A87; suivant : 003A89Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia
Auteurs : Jonathan Bond [Royaume-Uni, France] ; Renae Domaschenz [Royaume-Uni, Australie] ; M Nica Roman-Trufero [Royaume-Uni] ; Pierangela Sabbattini [Royaume-Uni] ; Isabel Ferreiros-Vidal [Royaume-Uni] ; Gareth Gerrard [Royaume-Uni] ; Vahid Asnafi [France] ; Elizabeth Macintyre [France] ; Matthias Merkenschlager [Royaume-Uni] ; Niall Dillon [Royaume-Uni]Source :
- Oncotarget [ 1949-2553 ] ; 2016.
Abstract
Ikaros and Foxp1 are transcription factors that play key roles in normal lymphopoiesis and lymphoid malignancies. We describe a novel physical and functional interaction between the proteins, which requires the central zinc finger domain of Ikaros. The Ikaros-Foxp1 interaction is abolished by deletion of this region, which corresponds to the IK6 isoform that is commonly associated with high-risk acute lymphoblastic leukemia (ALL). We also identify the
Url:
DOI: 10.18632/oncotarget.11688
PubMed: 27588474
PubMed Central: 5323203
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xml:lang="fr">France</country><wicri:regionArea> Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de Rrecherche Médicale (INSERM), and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Merkenschlager, Matthias" sort="Merkenschlager, Matthias" uniqKey="Merkenschlager M" first="Matthias" last="Merkenschlager">Matthias Merkenschlager</name><affiliation wicri:level="1"><nlm:aff id="A2"> Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Lymphocyte Development Group, MRC Clinical Sciences 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0NN</wicri:regionArea><wicri:noRegion>London W12 0NN</wicri:noRegion></affiliation><affiliation wicri:level="3"><nlm:aff id="A4"> Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de Rrecherche Médicale (INSERM), and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea> Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de Rrecherche Médicale (INSERM), and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Domaschenz, Renae" sort="Domaschenz, Renae" uniqKey="Domaschenz R" first="Renae" last="Domaschenz">Renae Domaschenz</name><affiliation wicri:level="1"><nlm:aff id="A1"> Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN</wicri:regionArea><wicri:noRegion>London W12 0NN</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="A5"> Present address: Chromatin and Transcriptional Regulation Group, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea> Present address: Chromatin and Transcriptional Regulation Group, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory</wicri:regionArea><wicri:noRegion>Australian Capital Territory</wicri:noRegion></affiliation></author><author><name sortKey="Roman Trufero, M Nica" sort="Roman Trufero, M Nica" uniqKey="Roman Trufero M" first="M Nica" last="Roman-Trufero">M Nica Roman-Trufero</name><affiliation wicri:level="1"><nlm:aff id="A1"> Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN</wicri:regionArea><wicri:noRegion>London W12 0NN</wicri:noRegion></affiliation></author><author><name sortKey="Sabbattini, Pierangela" sort="Sabbattini, Pierangela" uniqKey="Sabbattini P" first="Pierangela" last="Sabbattini">Pierangela Sabbattini</name><affiliation wicri:level="1"><nlm:aff id="A1"> Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN</wicri:regionArea><wicri:noRegion>London W12 0NN</wicri:noRegion></affiliation></author><author><name sortKey="Ferreiros Vidal, Isabel" sort="Ferreiros Vidal, Isabel" uniqKey="Ferreiros Vidal I" first="Isabel" last="Ferreiros-Vidal">Isabel Ferreiros-Vidal</name><affiliation wicri:level="1"><nlm:aff id="A2"> Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN</wicri:regionArea><wicri:noRegion>London W12 0NN</wicri:noRegion></affiliation></author><author><name sortKey="Gerrard, Gareth" sort="Gerrard, Gareth" uniqKey="Gerrard G" first="Gareth" last="Gerrard">Gareth Gerrard</name><affiliation wicri:level="1"><nlm:aff id="A3"> Imperial Molecular Pathology, Imperial College Academic Health Sciences Centre, Hammersmith Campus, London W12 0NN, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Imperial Molecular Pathology, Imperial College Academic Health Sciences Centre, Hammersmith Campus, London W12 0NN</wicri:regionArea><wicri:noRegion>London W12 0NN</wicri:noRegion></affiliation></author><author><name sortKey="Asnafi, Vahid" sort="Asnafi, Vahid" uniqKey="Asnafi V" first="Vahid" last="Asnafi">Vahid Asnafi</name><affiliation wicri:level="3"><nlm:aff id="A4"> Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de Rrecherche Médicale (INSERM), and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea> Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de Rrecherche Médicale (INSERM), and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Macintyre, Elizabeth" sort="Macintyre, Elizabeth" uniqKey="Macintyre E" first="Elizabeth" last="Macintyre">Elizabeth Macintyre</name><affiliation wicri:level="3"><nlm:aff id="A4"> Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de Rrecherche Médicale (INSERM), and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea> Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de Rrecherche Médicale (INSERM), and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Merkenschlager, Matthias" sort="Merkenschlager, Matthias" uniqKey="Merkenschlager M" first="Matthias" last="Merkenschlager">Matthias Merkenschlager</name><affiliation wicri:level="1"><nlm:aff id="A2"> Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN</wicri:regionArea><wicri:noRegion>London W12 0NN</wicri:noRegion></affiliation></author><author><name sortKey="Dillon, Niall" sort="Dillon, Niall" uniqKey="Dillon N" first="Niall" last="Dillon">Niall Dillon</name><affiliation wicri:level="1"><nlm:aff id="A1"> Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea> Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN</wicri:regionArea><wicri:noRegion>London W12 0NN</wicri:noRegion></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Ikaros and Foxp1 are transcription factors that play key roles in normal lymphopoiesis and lymphoid malignancies. We describe a novel physical and functional interaction between the proteins, which requires the central zinc finger domain of Ikaros. The Ikaros-Foxp1 interaction is abolished by deletion of this region, which corresponds to the IK6 isoform that is commonly associated with high-risk acute lymphoblastic leukemia (ALL). We also identify the <italic>Gpr132</italic> gene, which encodes the orphan G protein-coupled receptor G2A, as a novel target for Foxp1. Increased expression of Foxp1 enhanced <italic>Gpr132</italic> transcription and caused cell cycle changes, including G2 arrest. Co-expression of wild-type Ikaros, but not IK6, displaced Foxp1 binding from the <italic>Gpr132</italic> gene, reversed the increase in <italic>Gpr132</italic> expression and inhibited G2 arrest. Analysis of primary ALL samples revealed a significant increase in <italic>GPR132</italic> expression in <italic>IKZF1</italic>-deleted BCR-ABL negative patients, suggesting that levels of wild-type Ikaros may influence the regulation of G2A in B-ALL. Our results reveal a novel effect of Ikaros haploinsufficiency on Foxp1 functioning, and identify G2A as a potential modulator of the cell cycle in Ikaros-deleted B-ALL.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Georgopoulos, K" uniqKey="Georgopoulos K">K Georgopoulos</name></author><author><name sortKey="Moore, D" uniqKey="Moore D">D Moore</name></author><author><name sortKey="Derfler, B" uniqKey="Derfler B">B Derfler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lo, K" uniqKey="Lo K">K Lo</name></author><author><name sortKey="Landau, Nr" uniqKey="Landau N">NR Landau</name></author><author><name sortKey="Smale, St" uniqKey="Smale S">ST Smale</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Georgopoulos, K" uniqKey="Georgopoulos K">K Georgopoulos</name></author><author><name sortKey="Winandy, S" uniqKey="Winandy S">S Winandy</name></author><author><name 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