The cytokine network in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a highly heterogeneous malignancy of the blood and bone marrow, characterized by clonal expansion of myeloid stem and progenitor cells and rapid disease progression. Chemotherapy has been the first-line treatment for AML for more than 30 years. Application of recent high-throughput next-generation sequencing technologies has revealed significant molecular heterogeneity to AML, which in turn has motivated efforts to develop new, targeted therapies. However, due to the high complexity of this disease, including multiple driver mutations and the coexistence of multiple competing tumorigenic clones, the successful incorporation of these new agents into clinical practice remains challenging. These continuing difficulties call for the identification of innovative therapeutic approaches that are effective for a larger cohort of AML patients. Recent studies suggest that chronic immune stimulation and aberrant cytokine signaling act as triggers for AML initiation and progression, facets of the disease which might be exploited as promising targets in AML treatment. However, despite the greater appreciation of cytokine profiles in AML, the exact functions of cytokines in AML pathogenesis are not fully understood. Therefore, unravelling the molecular basis of the complex cytokine networks in AML is a prerequisite to develop new therapeutic alternatives based on targeting cytokines and their receptors.

Keywords: acute myeloid leukemia; cytokine inhibitors; cytokine signaling; inflammation; tumor microenvironment.

Figure 1

Cytokines supporting AML progression. Osteoblasts, myeloblasts and mesenchymal stromal cells (MSCs) secrete osteopontin. This in turn promotes AML cell proliferation and disease progression. CXCL12 is mainly secreted by perivascular stromal cells (PSCs), and osteoblasts and promotes growth and survival of AML blasts cell via the chemokine receptor CXCR4. IL-1β acts on myeloblasts and HSPCs, which express the IL-1 receptor (IL-1R) as well as the IL-1 receptor accessor protein (IL-1RAP), thereby enhancing IL-1β production, AML cell proliferation and survival. IL-1 signaling can be blocked by Canakinumab, a human monoclonal antibody targeting IL-1β. IL-8 is constitutively produced by AML myeloblasts and acts in an autocrine way. MSCs and myeloblasts are potent sources of IL-6, which can be blocked by IL-6-blocking antibodies such as Siltuximab. Created with Biorender.com.