Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Rabigh, Saudi Arabia.
Eur Rev Med Pharmacol Sci. 2022 Nov;26(22):8451-8458. doi: 10.26355/eurrev_202211_30381.
Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation is initiated by mutations in the JAK2 gene. This activation is in turn, a vital pathogenetic mechanism in myeloproliferative neoplasms (MPNs). However, several factors affect the pathogenesis of MPNs other than the JAK2 gene mutations, such as the downregulation of cytokine signaling (SOCS) proteins, which are potent inhibitors of the JAK/STAT pathway. Therefore, we hypothesized that the regulation of SOCS protein system might be a possible pathogenetic mechanism of MPNs through activating the JAK/STAT pathway.
Our study aimed to investigate the status of the Suppressors of cytokine signaling 1 (SOCS1) in 125 MPNs specimens at the level of mutated points. The acquired mutations, aberrant expression, and/or CpG island hypermethylation of SOCS1 were analyzed among Philadelphia-negative myeloproliferative neoplasm patients.
SOCS1 was identified in 20.0% of all patients with Philadelphia-negative myeloproliferative neoplasm. At the diagnosis, the prevalence of methylation was 41.0% for Polycythaemia Vera (PV), 27.7% for Essential Thrombocythaemia (ET), and 6.6% for Primary Myelofibrosis (PMF). The methylation was not detected in 20 healthy adult people. A significant association was found between disease groups (p=.077). The presence of methylated SOCS1 was found to be significantly correlated with age (p=.005), total RBCs count (p=.019), hemoglobin (Hb) concentration (p=.002), and Hematopoietic cell transplant (HCT) (p=.007) in PV patients. However, the presence of methylated SOCS1 was found to be significantly associated with age (p=.012), total RBCs count (p=.022), Hb concentration (p=.024), HCT (p=.033), and platelets count (p=.037) in ET patients. Moreover, the presence of methylated SOCS1 was significantly associated with Hb concentration (p=.046) and HCT (p=.040) in PMF patients.
We concluded that the activation of the JAK/STAT signaling pathway in alternative or with JAK2 mutations leads to SOCS1 hypermethylation, which could represent a potential therapeutic target.
Janus 激酶/信号转导和转录激活因子（JAK/STAT）通路的激活是由 JAK2 基因的突变引发的。这种激活是骨髓增殖性肿瘤（MPN）的重要发病机制。然而，除了 JAK2 基因突变之外，还有其他几个因素会影响 MPN 的发病机制，例如细胞因子信号转导（SOCS）蛋白的下调，SOCS 蛋白是 JAK/STAT 通路的有效抑制剂。因此，我们假设 SOCS 蛋白系统的调节可能是通过激活 JAK/STAT 通路导致 MPN 的潜在发病机制之一。
我们的研究旨在调查 125 例 MPN 标本中 Suppressors of cytokine signaling 1（SOCS1）的突变点水平的状态。分析费城阴性骨髓增殖性肿瘤患者中 SOCS1 的获得性突变、异常表达和/或 CpG 岛超甲基化。
SOCS1 在所有费城阴性骨髓增殖性肿瘤患者中占 20.0%。在诊断时，PV 的甲基化患病率为 41.0%，ET 为 27.7%，PMF 为 6.6%。20 名健康成年人未检测到甲基化。疾病组之间存在显著相关性（p=.077）。发现 SOCS1 的甲基化与 PV 患者的年龄（p=.005）、总 RBC 计数（p=.019）、血红蛋白（Hb）浓度（p=.002）和造血细胞移植（HCT）（p=.007）显著相关。然而，在 ET 患者中，SOCS1 的甲基化与年龄（p=.012）、总 RBC 计数（p=.022）、Hb 浓度（p=.024）、HCT（p=.033）和血小板计数（p=.037）显著相关。此外，在 PMF 患者中，SOCS1 的甲基化与 Hb 浓度（p=.046）和 HCT（p=.040）显著相关。
我们得出结论，JAK/STAT 信号通路的激活在替代或与 JAK2 突变一起导致 SOCS1 高甲基化，这可能代表一个潜在的治疗靶点。
