Page 49 - Haematologica Vol. 109 - July 2024

REVIEW ARTICLE - CXCL8 in primary myelofibrosis G. Vermeersch et al.
Figure 2. Overview of primary myelofibrosis pathophysiology. The role of inherited genetic variants is incompletely understood in primary myelofibrosis (PMF) and other BCR::ABL1 negative myeloproliferative neoplasms (MPN) but may contribute to an in- creased susceptibility of acquiring somatic mutations or chronic inflammatory states. Acquired somatic mutations may occur in key driver genes encoding Janus Kinase 2 (JAK2), the thrombopoietin receptor (MPL) or calreticulin (CALR) or may contribute to the development of clonal hematopoiesis of intermediate potential (CHIP), of which the pathophysiological role in MPN is also not completely understood. PMF, like other MPN, is associated with a chronic hyperinflammatory state characterized by increased concentrations of chemokines, cytokines, such as tumor necrosis factor-alpha (TNF-α) and growth factors. These may contribute to cellular proliferation, clonal evolution and megakaryocyte dysplasia, or may directly stimulate fibrosis through interaction with fibroblasts/mesenchymal cells. Direct immunologic cytotoxicity through release of reactive oxygen/nitrogen species (ROS/RNS) by activated leukocytes (e.g., downstream of TLR sensing of damage associated molecular pattern molecules [DAMP]) may be another pathway resulting in genotoxic stress or megakaryocyte dysplasia. Whether neutrophil engulfment by megakaryocytes (i.e., emperipolesis) directly contributes to megakaryocyte dysplasia remains to be elucidated. Clonal evolution may eventually result in blast transformation or secondary acute myeloid leukemia (sAML). Aberrant megakaryocytes show increased secretion of cytokines such as CXCL8 (interleukin-8 [IL-8]) or transforming growth factor-b (TGF-b) which contribute to the development of PMF.
TA1low mice, the use of reparixin, which acts as an inhibi- tor of the CXCL8 receptors CXCR1/CXCR2, or anti-CD62P antibodies combined with ruxolitinib resulted in reduced chemotaxis of neutrophils and decreased emperipolesis between neutrophils and megakaryocytes.26,27 Within mouse models not mimicking PMF pathophysiology, the use of CD18 antibodies also reduced neutrophil-megakaryocyte emperipolesis, while blocking antibodies against other membrane targets such as CD62P and CXCR2 appeared to have no effect.20,28 It is important to mention that, in 2019, the ADORE trial investigated the clinical efficacy of 5 dif- ferent agents, amongst which the monoclonal anti-CD62P antibody crizanlizumab, in combination with ruxolitinib. Unfortunately, the study was suspended in 2022 after an interim-analysis.29
Inflammatory signaling and cytokine profiling in myelofibrosis
Myeloproliferative neoplasms may be considered to be typ- ical inflammation-related malignancies, with, notably, PMF as the subtype associated with the highest inflammatory burden. Previous research tried to identify whether specific cytokine signatures correlate with MPN subtypes. However, most of those studies provided heterogenous results and primarily focused on PB plasma.4 Nonetheless, as cytokine functionality may be dose-dependent, some cytokines may be relevant at the BM level, whereas their concentration within PB plasma may be less relevant. Focusing solely on PB concentrations may thus result in the incorrect neglect of potential cytokines contributing within BM pathophys-
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