The expression of leukotriene B4 type‐1 receptor, BLT1, is facilitated by AML1 in leukocytes

Abstract

Leukotriene B4 (LTB4) is a lipid mediator that activates leukocytes through a specific G protein‐coupled receptor, BLT1. BLT1 plays important roles in host defense and pathogenesis of inflammatory and immune diseases. BLT1 is exclusively expressed in peripheral leukocytes, suggesting that its expression is stringently regulated. However, the precise mechanism of BLT1 expression is not fully understood. Here, we show that acute myeloid leukemia 1 (AML1/Runx1) is involved in the enhancement of BLT1 expression in leukocytes. In retinoic acid (RA)‐stimulated HL‐60 cells, the transcription of the BLT1 gene is significantly activated. RA did not directly modulate the BLT1 promoter, suggesting an enhancer(s) in other loci. DNase I‐hypersensitivity analyses revealed an activated region, termed AE‐BLex, at the intron‐I:exon‐II boundary. AE‐BLex acts as an enhancer for the BLT1 promoter and possesses two AML1 recognition sites. We demonstrated that the enhancement of BLT1 expression during the RA‐induced differentiation of HL‐60 cells is due to a loosening of the chromatin structure around AE‐BLex, which leads to the incremental binding of AML1. The AML1/AE‐BLex complex was confirmed in other BLT1‐expressing leukemia cell lines and human peripheral leukocytes. Thus, AML1 enhances BLT1 expression by binding to AE‐BLex, which is accessible in leukocytes.