Abstract

Lipocalin 24p3 is a secreted protein that can induce apoptosis in cells containing the 24p3 cell surface receptor, 24p3R. The oncoprotein BCR–ABL activates 24p3 and represses 24p3R expression. Thus, BCR–ABL⁺ cells synthesise and secrete 24p3, which induces apoptosis in normal 24p3R-containing cells but not in BCR–ABL⁺ cells. The cell signalling and transcription factor pathways by which BCR–ABL misregulates expression of 24p3 and 24p3R remain to be elucidated. Here we show that BCR–ABL upregulates 24p3 expression through activation of the JAK/STAT pathway, which culminates in binding of Stat5 to the 24p3 promoter. We find that 24p3R expression is regulated by Runx transcription factors, and that BCR–ABL induces a switch in binding from Runx3, an activator of 24p3R expression, to Runx1, a repressor of 24p3R expression, through a Ras signalling pathway. Finally, we show that repression of 24p3R by BCR–ABL is a critical feature of the mechanism by which imatinib kills BCR–ABL⁺ cells. Our results reveal diverse signalling/transcription pathways that regulate 24p3 and 24p3R expression in response to BCR–ABL and are directly relevant to the treatment of BCR–ABL⁺ disease.