Page 53 - Haematologica Vol. 109 - July 2024

REVIEW ARTICLE - CXCL8 in primary myelofibrosis
G. Vermeersch et al.
assays revealed an increased proportion of CXCL8 secreting CD34+ cells within patients with myelofibrosis compared to other MPN-subtypes. Patients with expanded CXCL8-secreting clones showed higher leukocytosis and higher-grade reticulin fibrosis compared to patients without these clones.6,66 CXCL8 negatively regulates healthy hematopoiesis, includ- ing megakaryopoiesis, through mechanisms that are still not completely understood.67-70 However, contradictory observations were made as other researchers showed enhanced cellular proliferation and fitness of MF-derived CD34+ cells co-cultured with exogenous CXCL8. It is still not known whether these differences might be explained by dose- or time-dependent mechanisms.6 The effects of CXCL8 on megakaryopoiesis are most likely mediated through CXCR1/2 signaling, as expression of both recep- tors was previously shown in megakaryocytes and mega- karyocyte progenitor cells.70,71 In contrast with CXCR1, the CXCR2 receptor appears over-expressed in CD34+ cells from patients with myelofibrosis compared to healthy controls.6,66 Interestingly, the use of neutralizing antibodies against either CXCL8, CXCR1 or CXCR2 resulted in increased megakaryocyte maturation and reduced ploidy.66 Recent findings also indicate a selective advantage of pre-malig- nant hematopoietic stem cell clones aberrantly expressing CXCL8 through increased interactions with the endothelial niche.72 Among 30 tested cytokines within PB of patients with PMF, increased CXCL8 concentrations predicted inferior leukemia-free survival and CXCL8 was the only cytokine associated with ≥1% circulating blasts.64 One of the mech- anisms preventing CXCL8-mediated activation of CD34+ progenitor cells might be the formation of heterodimers with CXCL4. CXCL4, also known as platelet factor-4 (PF-4), is a CXC chemokine and abundant α-granule protein within BM. The functional consequences of this heterodimeriza- tion vary; CXCL8 and CXCL4 synergize in the attraction of neutrophils, whereas the angiostatic activity of CXCL4 prevails above the angiogenic activity of CXCL8, likewise the binding of CXCL4 to CXCL8 inhibits CXCL8-mediated signaling in CD34+ progenitor cells.73,74 It has been proposed that high intramedullary concentrations of CXCL4 and CX- CL8 might promote extramedullary hematopoiesis, which is extensively present in PMF. Extramedullary hematopoi- esis notably involves the mobilization of hematopoietic, mesenchymal, and endothelial cells to so-called ‘new’ vascular niches within involved organs such as the spleen and liver. Although the exact mechanisms contributing to mobilization of these cells are still not fully understood, these extramedullary hematopoietic niches tend to play an important role in MPN progression.66,75,76 For example, in contrast to BM progenitor cells, it was previously shown that blood-derived CD34+ progenitors expanded and differ- entiated better when co-cultured with fibroblasts derived from myelometaplasic spleen compared to fibroblasts derived from normal BM.77 Within the GATA1low model, it has also been suggested that CD62P-dependent interac-
tion between neutrophils and megakaryocytes within the spleen mediates local production of TGF-b and thus the formation of a splenic environment supporting the prolif- eration of hematopoietic stem cells.22
The complex interplay between chemokines and hema- topoiesis in these different hematopoietic niches is far from completely understood but forms an essential field of research. It is important to emphasize that chemokines might act differently within these microenvironments, as chemokines tend to show context-dependent function- alities. Indeed, (hetero)dimerization, processing, synergy and/or antagonism may drastically affect chemokine ac- tivity and chemokines known as ‘inhibitory’ may become ‘stimulatory’.71,78
Angiogenesis and expression of proangiogenic factors, such as vascular endothelial growth factor (VEGF) are in- creased within the BM of MPN patients, especially in PMF. The JAK2 pathway tends to play a central role in PMF-as- sociated angiogenesis, as a strong positive correlation be- tween BM microvessel density and JAK2V617F mutant allele burden (≥55% mutant alleles) was found. Nonetheless, similar to hematopoiesis, angiogenesis in MPN involves multiple pathways, as microvessel density is increased in JAK2 negative cases as well, and mutated JAK2 is only present in approximately 50% of patients with PMF.4,79-81 Contrary to microvessel density, BM VEGF expression does not clearly correlate with JAK2V617F mutant allele burden.79 Besides these proangiogenic factors, chemokines such as CXCL8 are also known inducers of angiogenesis. All ELR+ CXC chemokines stimulate endothelial cell migration and proliferation, whereas CXCR3 binding chemokines that lack this ELR motif are angiostatic. CXCL8 stimulates angiogen- esis through its interaction with both CXCR1 and CXCR2 on endothelial cells, resulting in a 2-phase process, charac- terized by an early phase with the formation of actin stress fibers, and a later phase with cortical actin accumulation and cell retraction.82 Elevated cytokines in PMF, such as IL-1b induce CXCL8 and thus angiogenesis, while others, including interferon-α (IFN-α), IFN-b, and IFN-γ, up-regulate angiostatic CXCR3 ligands (CXCL9, CXCL10 and CXCL11).55,83
CXCR1/2 on neutrophils
CXCR1 and CXCR2 are key receptors mediating activation and chemotaxis of neutrophils. Researchers previously tried to reveal discriminating characteristics of both recep- tors through investigation of their downstream signaling pathways. CXCR1 plays a crucial role in the chemotaxis of neutrophils, as well as in the release of ROS and NET.45,84 The CXCL8-CXCR1/2 axis could thus play an important role in the increased NETosis observed in patients with MPN and its association with thrombosis.85 Nonetheless, current data on the role of NETosis in MPN-associated thrombosis is conflicting and beyond the scope of this review.85-87 Naïve
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