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Cancer Res. 2017 Jan 15;77(2):303-311. doi: 10.1158/0008-5472.CAN-16-1095. Epub 2016 Nov 21.

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

Author information

1
Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich, United Kingdom.
2
The Genome Analysis Centre (TGAC), Colney, Norwich, United Kingdom.
3
Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom.
4
Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich, United Kingdom. s.rushworth@uea.ac.uk k.bowles@uea.ac.uk.

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-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. Cancer Res; 77(2); 303-11.

PMID:
27872094
DOI:
10.1158/0008-5472.CAN-16-1095
[Indexed for MEDLINE]
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