title: Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia.
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.
authors: Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom.|Université 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.
authors: Jonathan
authors: J
authors: Bond
authors: Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom.|Present address: Chromatin and Transcriptional Regulation Group, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
authors: Renae
authors: R
authors: Domaschenz
authors: Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom.
authors: Mónica
authors: M
authors: Roman-Trufero
authors: Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom.
authors: Pierangela
authors: P
authors: Sabbattini
authors: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom.
authors: Isabel
authors: I
authors: Ferreiros-Vidal
authors: Imperial Molecular Pathology, Imperial College Academic Health Sciences Centre, Hammersmith Campus, London W12 0NN, United Kingdom.
authors: Gareth
authors: G
authors: Gerrard
authors: Université 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.
authors: Vahid
authors: V
authors: Asnafi
authors: Université 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.
authors: Elizabeth
authors: E
authors: Macintyre
authors: Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom.
authors: Matthias
authors: M
authors: Merkenschlager
authors: Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Campus, London W12 0NN, United Kingdom.
authors: Niall
authors: N
authors: Dillon
mesh_terms: D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; C115270:G2A receptor; C497239:IKZF1 protein, human; D043562:Receptors, G-Protein-Coupled; D012097:Repressor Proteins; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl
keywords: B cell cycle; Foxp1; GPR132; Ikaros; acute leukemia