AML1 enhances the expression of leukotriene B4 type-1 receptor in leukocytes

Leukotriene B(4) type-1 receptor (BLT1), which plays a role in various inflammatory diseases, is exclusively expressed in peripheral leukocytes, which suggests that its expression is stringently regulated. However, the precise mechanism of BLT1 expression is not fully understood. Here we report that acute myeloid leukemia 1 (AML1/Runx1) is involved in the enhancement of BLT1 expression in leukocytes. In retinoic acid (RA)-stimulated human promyelocytic leukemia (HL-60) cells, the transcription of the BLT1 gene was found to be significantly activated. RA did not directly modulate the BLT1 promoter, suggesting enhancers 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 2 AML1 recognition sites. The importance of AML1 was determined using electrophoretic mobility shift assays, reporter assays, and knockdown experiments. 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.