Page 48 - Haematologica Vol. 109 - July 2024

REVIEW ARTICLE - CXCL8 in primary myelofibrosis G. Vermeersch et al.
Figure 1. Overview of signaling pathways in myeloproliferative neoplasms. The Janus Kinase 2 (JAK2) protein is intracellularly connected with receptors such as the granulocyte-colony stimulating factor receptor (G-CSFR), the thrombopoietin receptor (myeloproliferative leukemia virus oncogene [MPL]), and erythropoietin receptor (EPOR). Activation of these receptors by their appropriate ligands (G-CSF, thrombopoietin [TPO] and EPO, respectively) induces phosphorylation of JAK2. Phosphorylated JAK2 serves as a docking station for signal transducer and activator of transcription 5 (STAT5) which initiates further downstream signaling pathways. Activated JAK2 may also stimulate the activation of other pathways such as mitogen activated protein-kinase (MAPK), phosphoinositide 3-kinase (PI3K) or the nuclear factor kappa B pathway (NF-κB) through activation of AKT (protein kinase B). NF-κB activation can also be mediated through activation of toll-like receptors (TLR) (not shown). Mutations in JAK2, calre- ticulin (CALR) or MPL genes result in uncontrolled activation of these proliferative pathways, enhanced cellular survival and production of various inflammatory cytokines, together promoting development of hematologic malignancies. Lightning symbol indicates occurrence of mutations in myeloproliferative neoplasm-associated driver genes (MPL, CALR and JAK2) coding for the corresponding proteins.
towards megakaryocyte characteristics in hematopoietic stem cells of patients with MPN.16 MPN-associated mega- karyocytes express low levels of the GATA1 transcription factor, which is associated with increased production of transforming growth factor (TGF)-b. TGF-b is a pleiotropic cytokine with anti-inflammatory but profibrotic properties, and stimulates production of collagen, fibronectin and ex- tracellular matrix. In addition to TGF-b, megakaryocytes in MPN show increased secretion of other cytokines, such as CXCL8, IL-6, and platelet-derived growth factor (Figure 2).17 Furthermore, histological analysis of BM from MPN pa- tients shows an increased incidence of megakaryocytes enclosing neutrophilic granulocytes, a phenomenon called emperipolesis. Emperipolesis appears to be preserved amongst mammalian species and is increased in conditions associated with systemic inflammation and high platelet demand. The phenomenon of megakaryocytes engulfing neutrophils was first described by Larsen in 1970, but the
exact biological role and molecular mechanism is still not fully understood.18,19 Emperipolesis is most likely mediated through multiple ligand-receptor interactions. Reduced in vitro emperipolesis is observed in megakaryocytes derived from mice deficient in intracellular adhesion molecule-1 (ICAM-1) and CD18.20 CD18 (also known as lymphocyte function-associated antigen 1 [LFA-1]) is a b2-integrin ex- pressed on neutrophils and is, through various interactions including with ICAM-1, a primary receptor involved in neu- trophil recruitment to inflamed environments.21 P-selectin, or CD62P, which is normally restricted to the α-granules, shows aberrant expression on the demarcation system of megakaryocytes within GATA1low mice. GATA1low mice function as a murine model of PMF, recapitulating the hyperactiva- tion of the TPO/MPL/JAK2 axis. Interestingly, within these mice, the deletion of CD62P disrupts interactions between neutrophils and megakaryocytes, and results in reduced concentrations of TGF-b and fibrosis.22-25 Moreover, in GA-
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