Masselli Elena, Carubbi Cecilia, Pozzi Giulia, Percesepe Antonio, Campanelli Rita, Villani Laura, Gobbi Giuliana, Bonomini Sabrina, Roti Giovanni, Rosti Vittorio, Massa Margherita, Barosi Giovanni, Vitale Marco
Department of Medicine and Surgery, Anatomy Unit, University of Parma, 43126 Parma, Italy.
Department of Medicine and Surgery, Genetics Unit, University of Parma, 43126 Parma, Italy.
Cancers (Basel). 2021 May 22;13(11):2552. doi: 10.3390/cancers13112552.
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.
单核苷酸多态性（SNPs）可改变个体的促炎背景，因此可能在以细胞因子异常产生为特征的骨髓增殖性肿瘤（MPN）环境中具有相关影响。在一个由773例原发性骨髓纤维化（PMF）患者组成的队列中，我们确定了CCL2（最有效的免疫调节趋化因子之一）的rs1024611 SNP对该疾病临床和生物学特征的影响，表明携带纯合子基因型G/G的男性受试者患PMF的风险增加，并且在PMF患者中，G/G基因型是总生存期缩短的独立预后因素。对PMF中该SNP和CCL2-CCR2轴的功能特性研究表明：i）与其他基因型相比，纯合子PMF细胞是趋化因子产生最多的细胞；ii）PMF CD34+细胞是CCL2的选择性靶点，因为它们独特地表达CCR2（CCL2受体）；iii）CCL2-CCR2轴的激活通过Akt磷酸化增强驱动突变诱导的促生存信号；iv）鲁索替尼可有效抑制PMF细胞中CCL2的产生并下调CCR2的表达。总之，CCL2/CCR2趋化因子系统在PMF中的作用的确定为该疾病的病理生理图景增添了一个新元素，具有临床和治疗意义。
