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 ORCID: https://orcid.org/0000-0003-1334-4526 (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
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	Pure Connector
Date Deposited:	30 Nov 2016 00:02
Last Modified:	28 Oct 2023 01:07
URI:	https://ueaeprints.uea.ac.uk/id/eprint/61525
DOI:	10.1158/0008-5472.CAN-16-1095

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