Role of IL8 in myeloid malignancies

Abstract

Aberrant overexpression of Interleukin-8 (IL8) has been reported in Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), Myeloproliferative Neoplasms (MPNs) and other myeloid malignancies. IL8 (CXCL8) is a CXC chemokine that is secreted by aberrant hematopoietic stem and progenitors as well as other cells in the tumor microenvironment. IL8 can bind to CXCR1/CXCR2 receptors and activate oncogenic signaling pathways, and also increase the recruitment of myeloid derived suppressor cells to the tumor microenvironment. IL8/CXCR1/2 overexpression has been associated with poorer prognosis in MDS and AML and increased bone marrow fibrosis in Myelofibrosis. Preclinical studies have demonstrated benefit of inhibiting the IL8/CXCR1/2 pathways via restricting the growth of leukemic stem cells as well as normalizing the immunosuppressive microenvironment in tumors. Targeting the IL8-CXCR1/2 pathway is a potential therapeutic strategy in myeloid neoplasms and is being evaluated with small molecule inhibitors as well as monoclonal antibodies in ongoing clinical trials. We review the role of IL8 signaling pathway in myeloid cancers and discuss future directions on therapeutic targeting of IL8 in these diseases.

Keywords:

• Leukemic stem cells
• MDS
• AML
• MPN
• IL8 inhibition

Author contributions

All authors contributed to the review. N.R and A.V conceived the idea of the review. N.R and A.V wrote the review. M.G, L.S, T.T. edited the review and A.S, B.W and U.S provided critical suggestions.

Disclosure statement

AV has received research funding from Prelude, BMS, GSK, Incyte, Medpacto, Curis and Eli Lilly and is a scientific advisor for Stelexis, Bakx, Novartis, Acceleron and Celgene and receives honoraria from Stelexis and Janssen and holds equity in Stelexis, Bakx and Throws Exception.

Figure 1. IL8 supports AML progression in the bone marrow. Leukemic stem cells (LSCs), Vascular endothelial cells and mesenchymal stem cells (MSCs) all have been shown to secrete IL8 (CXCL8). This in turn promotes AML proliferation and disease progression.

Figure 2. Pathways activated by IL8.

Additional information

Funding

A.V is funded by the Edward P. Evans Foundation, Leukemia Lymphoma Society and a grant from the Jane and Myles Dempsey Family.