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

Abdul-Aziz, Amina, Shafat, Manar, Mehta, Tarang, Di Palma, Federica, Lawes, Matthew, Rushworth, Stuart A and Bowles, Kristian (2017) MIF-induced stromal PKCβ/IL8 is essential in human acute myeloid leukemia. Cancer Research, 77 (2). pp. 303-311. ISSN 0008-5472

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    Abstract

    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.

    Item Type: Article
    Uncontrolled Keywords: mif,interleukin-8,pkc,aml,leukemia,microenvironment
    Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
    Faculty of Science
    Faculty of Science > School of Biological Sciences
    University of East Anglia > Faculty of Medicine and Health Sciences > Research Groups > Prostate Cancer Studies
    Depositing User: Pure Connector
    Date Deposited: 30 Nov 2016 00:02
    Last Modified: 25 Jul 2018 12:58
    URI: https://ueaeprints.uea.ac.uk/id/eprint/61525
    DOI: 10.1158/0008-5472.CAN-16-1095

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