Longitudinal Cytokine Profiling Identifies GRO‐α and EGF as Potential Biomarkers of Disease Progression in Essential Thrombocythemia

Abstract

Myeloproliferative neoplasms (MPNs) are characterized by deregulation of mature blood cell production and increased risk of myelofibrosis (MF) and leukemic transformation. Numerous driver mutations have been identified but substantial disease heterogeneity remains unexplained, implying the involvement of additional as yet unidentified factors. The inflammatory microenvironment has recently attracted attention as a crucial factor in MPN biology, in particular whether inflammatory cytokines and chemokines contribute to disease establishment or progression. Here we present a large-scale study of serum cytokine profiles in more than 400 MPN patients and identify an essential thrombocythemia (ET)-specific inflammatory cytokine signature consisting of Eotaxin, GRO-α, and EGF. Levels of 2 of these markers (GRO-α and EGF) in ET patients were associated with disease transformation in initial sample collection (GRO-α) or longitudinal sampling (EGF). In ET patients with extensive genomic profiling data (n = 183) cytokine levels added significant prognostic value for predicting transformation from ET to MF. Furthermore, CD56+CD14+ pro-inflammatory monocytes were identified as a novel source of increased GRO-α levels. These data implicate the immune cell microenvironment as a significant player in ET disease evolution and illustrate the utility of cytokines as potential biomarkers for reaching beyond genomic classification for disease stratification and monitoring.

Anti-Glucosylsphingosine Autoimmunity, JAK2V617F-Dependent Interleukin-1β and JAK2V617F-Independent Cytokines in Myeloproliferative Neoplasms

“…In addition, like HGF and TNF-α, recent studies suggest that IL-1β favors MPN disease initiation and clonal expansion [ 54 , 63 , 64 , 65 ]. In the context of ET, Øbro et al reported that GRO-α and EGF (not measured in our study) were potential markers of disease progression, independently of JAK2 V617F or CALR mutation [ 66 ]. To summarize, the data indicate that IL-1β, IL-1Rα and IP-10 are linked to JAK2 V617F mutation, whereas all other cytokines in excess in MPNs are produced independently of JAK2 and CALR mutations but differentially according to the MPN phenotype.…”

Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants

“…Of note, the main cellular source of GRO-α in ET has been identified in CD56+/CD14+ monocytes. Authors eventually introduced a novel prognostic model that incorporates cytokine profiling to well-established risk variables such as age, gender, and high-risk mutations [75]. As pointed out by Hasselbalch's commentary, this study highlights the prominent role of chronic inflammation in modulating MPN phenotype and course, and shows how the measurement of circulating cytokines may be an informative tool for patient risk stratification [76].…”

“…Then, if we compare PMF with ET and PV (Table 2), surprisingly, not all inflammatory mediators are increased. Indeed, of the 29 cytokines whose levels and/or expression have been investigated in PMF as compared to the other two MPNs, 15 are increased (IL-2, sIL-2R, IL-6, IL-12, IL-17, TNF-α, INF-α, IL1RA, IL-4, IL-10, MIP-1β, RANTES, FGF, TPO, TGF-β) [63,70,72,80], IL1-α is similar [63], MCP-1 similar or increased, according to different studies [72,80], five cytokines are decreased (IL-7, VEGF, MIG, GRO-α, and CCL11) [70,75,79], and five show contradictory findings (both increased and decreased according to different reports: INF-γ, MIP-1α, IP-10, GM-CSF, EGF) [70,72,75,80]. The only mediators that are steadily elevated are pro-fibrotic cytokines, such as TGF-β, MCP-1, and FGF ( Table 2), suggesting that while inflammation is a common denominator of all three MPNs, PMF is characterized by a unique fibrogenic cytokine signature.…”

Gene Expression of CXCL1 (GRO‐α) and EGF by Platelets in Myeloproliferative Neoplasms

“… 5 Our data reaffirms Øbro et al's observation that decreased levels of EGF is associated with progression to MF. 1 The expression levels for CCL11 (eotaxin) in platelets from all MPN subtypes were minimal and did not differ from controls. This is as expected, since eotaxin is mainly produced by structural and infiltrative inflammatory cells.…”

“…We read with interest the recent publication by Øbro et al in HemaSphere documenting elevated cytokine levels in patients with myeloproliferative neoplasms (MPN). 1 Specifically, their finding of a signature associated with essential thrombocythemia (ET) that included three biomarkers: GRO-α, EGF and eotaxin. GRO-α was of greatest interest as elevated levels were associated with disease transformation to myelofibrosis (MF).…”