title: MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia.
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.
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich, United Kingdom.
authors.forename: Amina M
authors.initials: AM
authors.lastname: Abdul-Aziz
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich, United Kingdom.
authors.forename: Manar S
authors.initials: MS
authors.lastname: Shafat
authors.affiliation: The Genome Analysis Centre (TGAC), Colney, Norwich, United Kingdom.
authors.forename: Tarang K
authors.initials: TK
authors.lastname: Mehta
authors.affiliation: The Genome Analysis Centre (TGAC), Colney, Norwich, United Kingdom.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Palma
authors.affiliation: Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lawes
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich, United Kingdom. s.rushworth@uea.ac.uk k.bowles@uea.ac.uk.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Rushworth
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich, United Kingdom. s.rushworth@uea.ac.uk k.bowles@uea.ac.uk.|Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, United Kingdom.
authors.forename: Kristian M
authors.initials: KM
authors.lastname: Bowles
mesh_terms: D015153:Blotting, Western; D002470:Cell Survival; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D064546:Protein Kinase C beta / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D008263:Macrophage Migration-Inhibitory Factors; D064546:Protein Kinase C beta; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human