Impact of the rs1024611 Polymorphism of CCL2 on the Pathophysiology and Outcome of Primary Myelofibrosis

Abstract

Single nucleotide polymorphisms (SNPs) can modify the individual pro-inflammatory background and may therefore have relevant implications in the MPN setting, typified by aberrant cytokine production. In a cohort of 773 primary myelofibrosis (PMF), we determined the contribution of the rs1024611 SNP of CCL2—one of the most potent immunomodulatory chemokines—to the clinical and biological characteristics of the disease, demonstrating that male subjects carrying the homozygous genotype G/G had an increased risk of PMF and that, among PMF patients, the G/G genotype is an independent prognostic factor for reduced overall survival. Functional characterization of the SNP and the CCL2-CCR2 axis in PMF showed that i) homozygous PMF cells are the highest chemokine producers as compared to the other genotypes; ii) PMF CD34+ cells are a selective target of CCL2, since they uniquely express CCR2 (CCL2 receptor); iii) activation of the CCL2-CCR2 axis boosts pro-survival signals induced by driver mutations via Akt phosphorylation; iv) ruxolitinib effectively counteracts CCL2 production and down-regulates CCR2 expression in PMF cells. In conclusion, the identification of the role of the CCL2/CCR2 chemokine system in PMF adds a novel element to the pathophysiological picture of the disease, with clinical and therapeutic implications.

CCL2 rs1024611Gene Polymorphism in Philadelphia-Negative Myeloproliferative Neoplasms

“…Moreover, the CCL2 rs1024611 SNP was significantly correlated to the CCL2 gene expression level and fibrosis grade. In accordance with our findings, Masselli et al [30] recorded that the G/G genotype significantly overexpressed CCL2 transcript compared to the A/A and the A/G genotypes and the G allele exerts its effect on CCL2 expression in a dose-dependent manner. In agreement with our findings, Wong and colleagues reported that the chemokine gene CCL2 was up-regulated threefold more in overtly fibrotic than in pre-fibrotic MPNs [31].…”

The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome

“…In combined analysis of the G/G genotype with other well-established clinical prognostic parameters included in the IPSS scoring system we found a significant correlation in both univariate and multivariate analysis. Finally, we determined the functional implication of this SNP in PMF, showing that higher CCL2 circulating levels, determined by the G/G rs1024611 genotype, are biologically relevant since PMF hematopoietic progenitors selectively express CCR2 and activate a pro-survival, Aktdependent signaling pathway when stimulated with CCL2 [60].…”

Utilizing Genomically Targeted Molecular Data to Improve Patient-Specific Outcomes in Autism Spectrum Disorder

“…This patient was also homozygous for another genomic variant that has been associated with elevated CCL2 (C-C motif chemokine ligand 2) levels [48]. Many natural products have been shown to lower CCL2 in the literature.…”