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Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia
Amina M Abdul-Aziz1, Manar S Shafat1, Tarang K Mehta2
1Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich, United Kingdom.
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. ©2016 AACR.
Insights
Bone marrow mesenchymal stromal cells (BM-MSCs) protect acute myeloid leukemia (AML) cells from apoptosis. A novel bidirectional mechanism involving macrophage migration inhibitory factor (MIF) and IL8 promotes AML survival within the tissue microenvironment.
Area of Science:
- Hematology
- Cancer Biology
- Cellular Microenvironment
Background:
- Acute myeloid leukemia (AML) cells show high in vitro apoptosis but prolonged in vivo survival, suggesting a critical role for the tissue microenvironment.
- Bone marrow mesenchymal stromal cells (BM-MSCs) are known to protect AML blasts from apoptosis.
- A novel interaction benefiting AML proliferation and survival was investigated.
Purpose of the Study:
- To elucidate a novel, bidirectional, prosurvival mechanism between AML blasts and BM-MSCs.
- To identify key molecular players in the AML-BM-MSC interaction.
- To provide a biologic rationale for targeting the AML microenvironment therapeutically.
Main Methods:
- Cytokine profiling of AML cells alone and co-cultured with BM-MSCs.
- Investigated the role of macrophage migration inhibitory factor (MIF) and IL8 in the AML-BM-MSC interaction.
- Utilized recombinant MIF, MIF inhibitor ISO-1, and IL8 shRNA to probe the mechanism.
- Examined the involvement of CD74 receptor and Protein Kinase C beta (PKCβ).
Main Results:
- Primary AML cells highly expressed MIF; co-culture with BM-MSCs increased IL8 expression.
- Recombinant MIF upregulated IL8 in BM-MSCs via CD74, a process regulated by PKCβ.
- The MIF inhibitor ISO-1 reduced AML-induced IL8 expression and BM-MSC-mediated AML survival.
- Targeted IL8 inhibition abrogated BM-MSC-induced AML cell survival.
Conclusions:
- A novel bidirectional prosurvival pathway exists between AML blasts and BM-MSCs involving MIF and IL8.
- This interaction is mediated by MIF secreted by AML cells, which induces IL8 production in BM-MSCs.
- Targeting the MIF/IL8 axis within the bone marrow microenvironment represents a potential therapeutic strategy for AML.
