Page 50 - Haematologica Vol. 109 - July 2024

REVIEW ARTICLE - CXCL8 in primary myelofibrosis
G. Vermeersch et al.
iology. There is increasing evidence that the presence of an inflammatory cytokine storm within the BM niche may trigger the development of myelofibrosis or even stimulate transformation into secondary AML. Only a select number of studies evaluated BM cytokine profiles in myelofibrosis compared to BM from other MPN subtypes or healthy con- trols. Previous studies demonstrated significantly increased levels of CXCL8, CXCL10 (interferon γ-induced protein 10 [IP-10]), IL-6Ra, IL-18, and TGF-b in BM of patients with PMF compared to healthy controls.4,30,31 Others measured consid- erably different cytokine concentrations in BM compared to PB. By example, one study investigating cytokine profiles in BM versus PB of 24 MPN patients reported significantly higher concentrations of 10 cytokines (IL-1ra, IL-1b, IL-7, IL-12p40, IL-15, IL-16, CXCL9 [monokine induced by γ interferon/MIG], macrophage colony-stimulating factor [M-CSF], granulocyte colony-stimulating factor [G-CSF], platelet-derived growth factor-BB [PDGF-BB]) and tissue inhibitor of metallopep- tidase inhibitor 1 (TIMP-1) in the BM niche. Compared to PB plasma from healthy controls, CXCL8 was significantly elevated in both PB plasma and BM of patients with MPN. However, no statistically significant differences in CXCL8 concentrations were observed between BM and PB from patients. As this study included only a limited number of patients (i.e., 4 with PMF), further studies are needed.32 Although constitutive activation of JAK-STAT appears to be a major player in the pathogenesis of MPN, current thera- peutic approaches inhibiting JAK2, such as ruxolitinib, seem to be ineffective in preventing evolution of the disease or avoiding transformation into secondary AML. Therefore, a role of other downstream signaling pathways in the hy- perproliferative state associated with MPN is suspected. This hypothesis is supported by other findings, amongst which the long latency between acquiring JAK2 mutational status and development of the disease, as well as the dif- ferent observed disease phenotypes and kinetics despite identical underlying mutation.12 Currently, allogeneic stem cell transplantation remains the only potentially curative treatment option for PMF. In addition, the often higher age of patients with PMF frequently limits the ability to use full intensity conditioning. However, it has to be mentioned that reduced-intensity regimens still offer significant survival advantages in these patients.33
Recent research shows persistent hyperactive nuclear fac- tor kappa-B (NF-κB) and MAPK signaling in patients with myelofibrosis treated with the JAK2-inhibitor ruxolitinib. Interestingly, the concentration of cytokines, including that of CXCL8, appears to be only minimally influenced by treatment with ruxolitinib.34 NF-κB hyperactivation was not only confined to CD34+ cells, but was observed through- out different myeloid and lymphoid cell populations. It is hypothesized that, through production of NF-κB-activating cytokines, NF-κB hyperactivation may be transmitted from malignant clones to non-malignant cells.35 NF-κB is a central transcriptional regulator of various inflammatory cytokines
aberrantly expressed in PMF, including CXCL8, TGF-b, and tumor necrosis factor-alpha (TNF-α). In general, 2 distinct NF-κB activation pathways, known as the classical and alternative pathways, can be distinguished. The classical, or canonical, NF-κB pathway is activated downstream of toll-like receptors (TLR), for example, activated by S100A8 and S100A9, or by cytokines (e.g., IL-1b and TNF-α) in an autocrine loop.5,36-38 Activation of the canonical pathway is associated with myeloproliferation in situations such as emergency hematopoiesis and myeloid malignancies. TLR are part of the innate immune system and function as pat- tern recognition receptors that recognize pathogen-associ- ated molecular patterns (PAMP) from microbial organisms and damage-associated molecular patterns (DAMP), such as S100A8/9 resulting from cellular damage.36 Release of TNF-α or DAMP may result in pyroptosis and necroptosis, which are different forms of programmed cell death and may further stimulate local inflammation through release of additional cytokines and DAMP (Figure 2).39,40 TNF-α can activate various downstream signaling pathways through binding with its receptors TNFRSF1a and TNFRSF1b (also known as TNFR1 and TNFR2). These receptors are, respec- tively, associated with either apoptosis or proliferation, both activating NF-κB pathways in their target cells. The dual functioning of TNF-α resulted in the hypothesis that TNF-α may promote clonal dominance by simultaneously inhibiting benign hematopoiesis while stimulating myelop- roliferation of the malignant clones.5 In mice, it has been shown that release of S100A8/9 results in genotoxic stress, and transcriptional activation of the S100A8/9-TLR pathway predicts leukemic evolution and progression-free survival in myelodysplastic syndromes (MDS).41 Basiorka et al. recently showed that the formation of large, filamentous clusters of apoptosis-associated speck-like protein containing a CARD (also known as PYCARD or ASC) adaptor protein might serve as a biomarker for pyroptotic cell death in MDS and correlates with S100A8/9 concentration. These clusters are called ASC specks and are released upon cytolysis. Within this study, no statistical differences were observed in patients with PMF; however, only 3 patients were includ- ed.42 Release of IL-1b has a direct, stimulatory effect on megakaryopoiesis, promotes polyploidization, and results in increased levels of profibrotic TGF-b. Pharmacological inhibition of IL-1b reduced myelofibrosis in a Jak2V617F mouse model and combination with ruxolitinib even resulted in complete reversal of fibrosis.43
CXCL8 and its cognate receptors CXCR1/2
The CXCL8 gene, composed of 4 exons and 3 introns, is located on chromosome 4 and codes for a precursor CX- CL8 protein of 99 amino acids.44 This precursor protein is eventually cleaved into a 77 amino acid (CXCL8(1-77)), or
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