MIF-induced stromal PKCβ/IL8 is essential in human acute myeloid leukemia

Acute myeloid leukemia (AML) cells exhibit a high level of spontaneous apoptosis when cultured in vitro but have a prolonged survival time in vivo, indicating that tissue microenvironment plays a critical role in promoting AML cell survival. In vitro studies have shown that bone marrow-mesenchymal stromal cells (BM-MSC) protect AML blasts from spontaneous and chemotherapy-induced apoptosis. Here we report a novel interaction between AML blasts and BM-MSC which benefits AML proliferation and survival. We initially examined the cytokine profile in cultured human AML compared to AML cultured with BMMSC and found that macrophage-migration inhibitory factor (MIF) was highly expressed by primary AML, and that interleukin-8 (IL-8) was increased in AML/BM-MSC co-cultures. Recombinant MIF increased IL-8 expression in BM-MSC via its receptor CD74. Moreover, the MIF inhibitor ISO-1 inhibited AML-induced IL-8 expression by BM-MSC as well as BMMSC- induced AML survival. Protein kinase C β (PKCβ) regulated MIF-induced IL-8 in BMMSC. Finally, targeted IL-8 shRNA inhibited BM-MSC-induced AML survival. These results describe a novel, bidirectional, pro-survival mechanism between AML blasts and BM-MSC. Furthermore, they provide biologic rationale for therapeutic strategies in AML targeting the
microenvironment, specifically MIF and IL-8.