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.