Data from MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

Abstract

<div>Abstract<p>Acute myeloid leukemia (AML) cells exhibit a high level of spontaneous apoptosis when cultured <i>in vitro</i> but have a prolonged survival time <i>in vivo</i>, indicating that tissue microenvironment plays a critical role in promoting AML cell survival. <i>In vitro</i> 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-MSCs, which benefits AML proliferation and survival. We initially examined the cytokine profile in cultured human AML compared with AML cultured with BM-MSCs and found that macrophage migration inhibitory factor (MIF) was highly expressed by primary AML, and that IL8 was increased in AML/BM-MSC cocultures. Recombinant MIF increased IL8 expression in BM-MSCs via its receptor CD74. Moreover, the MIF inhibitor ISO-1 inhibited AML-induced IL8 expression by BM-MSCs as well as BM-MSC–induced AML survival. Protein kinase C β (PKCβ) regulated MIF-induced IL8 in BM-MSCs. Finally, targeted IL8 shRNA inhibited BM-MSC–induced AML survival. These results describe a novel, bidirectional, prosurvival mechanism between AML blasts and BM-MSCs. Furthermore, they provide biologic rationale for therapeutic strategies in AML targeting the microenvironment, specifically MIF and IL8. <i>Cancer Res; 77(2); 303–11. ©2016 AACR</i>.</p></div>