Page 46 - Haematologica Vol. 109 - July 2024

REVIEW ARTICLE
CXCL8 and its cognate receptors CXCR1/CXCR2 in primary myelofibrosis
Gaël Vermeersch,1,2 Paul Proost,2 Sofie Struyf,2 Mieke Gouwy2 and Timothy Devos1,2
1Department of Hematology, University Hospitals Leuven and 2Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
Abstract
BCR::ABL1 negative myeloproliferative neoplasms (MPN) 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 MPN. Addi- tionally, for a significant subset of patients, MPN evolve 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 (BM) and peripheral blood (PB), MPN may be considered to be typical inflammation-related malignan- cies. However, the exact role and consequences of increased cytokine concentrations within BM and PB plasma has still not been completely established. Up-regulated cytokines can stimulate cellular proliferation, or contribute to the devel- opment of an inflammation-related BM niche resulting in genotoxicity and thereby supporting mutagenesis. The neutrophil chemoattractant CXCL8 is of specific interest as its concentration is increased within PB and BM 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 BM fibrosis and megakaryocyte dysmorphia in murine models. In this review, we sum- marize 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.
Introduction
BCR::ABL1 negative myeloproliferative neoplasms (MPN) constitute a distinct group of hematologic malignancies characterized by sustained proliferation of cells from mul- tiple myeloid lineages. Within MPN, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are the 3 most common entities. PV is character- ized by panmyelosis, ET by thrombocytosis, while PMF can present with various changes in blood cell count and is characterized by extensive formation of fibrous tissue within the bone marrow (BM). Most patients with MPN harbor mutually exclusive somatic mutations, which con- stitutively activate signal transducing pathways resulting in uncontrolled cellular proliferation. The genes Janus kinase 2 (JAK2), myeloproliferative leukemia virus onco-
gene (MPL), and calreticulin (CALR) are the most affected with mutational frequencies varying amongst different MPN subtypes. Within all subtypes, JAK2V617F is the most common mutation with a reported frequency of approx- imately 95% in patients with PV, 60% in ET, and 50% in PMF. Additionally, roughly 30% of patients with PMF harbor mutations in the CALR gene and 10% in the MPL gene. A small percentage of patients with PMF are considered triple negative, which indicates the absence of mutated JAK2, CALR or MPL.1 While the majority show slow progression, for a subset of patients, MPN rapidly evolve into BM failure or they develop secondary acute myeloid leukemia (AML) (frequency 10-15%), also called MPN blast phase.2 Patients with PMF show highly variable survival rates, ranging from several decades to a median survival of 16-35 months for patients with high-risk disease.3
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Correspondence: T. Devos timothy.devos@uzleuven.be
Received: Accepted: Early view:
December 27, 2023. February 16, 2024. February 29, 2024.
https://doi.org/10.3324/haematol.2023.284921
©2024 Ferrata Storti Foundation Published under a CC BY-NC license