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

// Jonathan Bond 1, 4, * , Renae Domaschenz 1, 5, * , Monica Roman-Trufero 1 , Pierangela Sabbattini 1 , Isabel Ferreiros-Vidal 2 , Gareth Gerrard 3 , Vahid Asnafi 4 , Elizabeth Macintyre 4 , Matthias Merkenschlager 2 , Niall Dillon 1 1 Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom 2 Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom 3 Imperial Molecular Pathology, Imperial College Academic Health Sciences Centre, Hammersmith Campus, London W12 0NN, United Kingdom 4 Universite Paris Descartes Sorbonne Cite, Institut Necker-Enfants Malades (INEM), Institut National de Recherche Medicale (INSERM), and Laboratory of Onco-Hematology, Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Necker Enfants-Malades, Paris, France 5 Present 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.