An Arc-regulated IL1B/COX-2/PGE2/ b-catenin/arc circuit controls leukemia–microenvironment interactions and confers drug resistance in AML

The apoptosis repressor with caspase recruitment domain (ARC) protein is a strong independent adverse prognostic marker in acute myeloid leukemia (AML). We previously reported that ARC regulates leukemia–microenvironment interactions through the NFkB/IL1b signaling network. Malignant cells have been reported to release IL1b, which induces PGE2 synthesis in mesenchymal stromal cells (MSC), in turn activating b-catenin signaling and inducing the cancer stem cell phenotype. Although Cox-2 and its enzymatic product PGE2 play major roles in inflammation and cancer, the regulation and role of PGE2 in AML are largely unknown. Here, we report that AML–MSC cocultures greatly increase Cox-2 expression in MSC and PGE2 production in an ARC/IL1b–dependent manner. PGE2 induced the expression of b-catenin, which regulated ARC and augmented chemoresistance in AML cells; inhibition of b-catenin decreased ARC and sensitized AML cells to chemotherapy. NOD/SCIDIL2RgNull-3/GM/SF mice transplanted with ARC-knockdown AML cells had significantly lower leukemia burden, lower serum levels of IL1b/PGE2, and lower tissue human ARC and b-catenin levels, prolonged survival, and increased sensitivity to chemotherapy than controls. Collectively, we present a new mechanism of action of antiapoptotic ARC by which ARC regulates PGE2 production in the tumor microenvironment and microenvironment-mediated chemoresistance in AML.