Journal
CANCER RESEARCH
Volume 77, Issue 2, Pages 303-311Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-16-1095
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Funding
- Worldwide Cancer Research
- Big C
- National Institutes for Health Research (United Kingdom)
- Ministry of Higher Education and Scientific Research of the State of Libya
- Biotechnology and Biological Sciences Research Council [BBS/E/T/000PR5885, BBS/E/T/000PR6193, BBS/E/T/000PR9819] Funding Source: researchfish
- BBSRC [BBS/E/T/000PR6193, BBS/E/T/000PR9819, BBS/E/T/000PR5885] Funding Source: UKRI
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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 BMMSCs via its receptor CD74. Moreover, the MIF inhibitor ISO1 inhibited AML-induced IL8 expression by BM-MSCs as well as BM-MSC-induced AML survival. Protein kinase C beta (PKC beta) 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. (C) 2016 AACR.
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