Oncotarget

Research Papers:

Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia

Jonathan Bond, Renae Domaschenz, Mónica Roman-Trufero, Pierangela Sabbattini, Isabel Ferreiros-Vidal, Gareth Gerrard, Vahid Asnafi, Elizabeth Macintyre, Matthias Merkenschlager and Niall Dillon _

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Oncotarget. 2016; 7:65923-65936. https://doi.org/10.18632/oncotarget.11688

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Abstract

Jonathan Bond1,4,*, Renae Domaschenz1,5,*, Mónica Roman-Trufero1, Pierangela Sabbattini1, Isabel Ferreiros-Vidal2, Gareth Gerrard3, Vahid Asnafi4, Elizabeth Macintyre4, Matthias Merkenschlager2, Niall Dillon1

1Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom

2Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom

3Imperial Molecular Pathology, Imperial College Academic Health Sciences Centre, Hammersmith Campus, London W12 0NN, United Kingdom

4Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut National de Recherche Médicale (INSERM), and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France

5Present address: Chromatin and Transcriptional Regulation Group, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia

*These authors have contributed equally to this work

Correspondence to:

Niall Dillon, email: niall.dillon@csc.mrc.ac.uk

Keywords: Ikaros, Foxp1, GPR132, B cell cycle, acute leukemia

Received: February 22, 2016    Accepted: August 13, 2016    Published: August 30, 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 Gpr132 gene, which encodes the orphan G protein-coupled receptor G2A, as a novel target for Foxp1. Increased expression of Foxp1 enhanced Gpr132 transcription and caused cell cycle changes, including G2 arrest. Co-expression of wild-type Ikaros, but not IK6, displaced Foxp1 binding from the Gpr132 gene, reversed the increase in Gpr132 expression and inhibited G2 arrest. Analysis of primary ALL samples revealed a significant increase in GPR132 expression in IKZF1-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.


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