CXCL8 and its cognate receptors CXCR1/CXCR2 in primary myelofibrosis.

Abstract

BCR::ABL1 negative myeloproliferative neoplasms (MPNs) form a distinct group of hematologic malignancies characterized by sustained proliferation of cells from multiple myeloid lineages. With a median survival of 16-35 months in patients with high-risk disease, primary myelofibrosis (PMF) is considered the most aggressive entity amongst all BCR::ABL1 MPNs. Additionally, a significant subset of patients evolves into secondary acute myeloid leukemia (AML) which has an even poorer prognosis compared to de novo AML. As the exact mechanisms of disease development and progression remain to be elucidated, current therapeutic approaches fail to prevent disease progression or transformation into secondary AML. As each MPN entity is characterized by sustained activation of various immune cells and raised cytokine concentrations within bone marrow and peripheral blood, MPNs may be considered as typical inflammation-related malignancies. However, the exact role and consequences of increased cytokine concentrations within bone marrow and peripheral blood plasma are currently incompletely established. Upregulated cytokines can stimulate cellular proliferation or contribute to the development of an inflammation-related bone marrow niche resulting in genotoxicity and thereby supporting mutagenesis. The neutrophil chemoattractant CXCL8 is of specific interest as its concentration is increased within peripheral blood and bone marrow plasma of patients with PMF. Increased concentration of CXCL8 negatively correlates with overall survival. Furthermore, blockage of the CXCR1/2 axis appears to be able to reduce bone marrow fibrosis and megakaryocyte dysmorphia in murine models. Within this review, we summarize available evidence on the role of the CXCL8-CXCR1/2 axis within the pathogenesis of PMF and discuss potential therapeutic modalities targeting either CXCL8 or its cognate receptors CXCR1/2.