Todor Samuel B, Mihaila Romeo Gabriel
Faculty of Medicine, "Lucian Blaga" University of Sibiu, 550024 Sibiu, Romania.
J Clin Med. 2025 Sep 8;14(17):6328. doi: 10.3390/jcm14176328.
Philadelphia-negative myeloproliferative neoplasms (Ph-MPNs) are clonal hematologic malignancies characterized not only by driver mutations such as JAK2V617F, CALR, and MPL but also by a profoundly dysregulated immune microenvironment. Chronic inflammation and immune remodeling sustain malignant hematopoiesis and contribute to disease progression from essential thrombocythemia (ET) and polycythemia vera (PV) to overt myelofibrosis (MF). Pro-inflammatory cytokines and chemokines-including IL-2, IFN-α, IL-23, and TNF-α-drive abnormal T cell polarization, favoring a pathogenic Th17 phenotype. Lymphocyte subset analysis reveals a predominance of exhausted PD-1 T cells, reflecting impaired immune surveillance. Concurrently, alterations in neutrophil apoptosis lead to persistent inflammation and stromal activation. GRO-α (CXCL1) is elevated in ET but reduced in MF, suggesting a subtype-specific role in disease biology. Fibrosis-promoting factors such as TGF-β and IL-13 mediate bone marrow remodeling and megakaryocyte expansion, while VEGF and other angiogenic factors enhance vascular niche alterations, particularly in PV. These immunopathologic features underscore novel therapeutic vulnerabilities. In addition to JAK inhibition, targeted strategies such as CXCR1/2 antagonists, anti-TGF-β agents, and immune checkpoint inhibitors (PD-1/PD-L1 blockade) may offer disease-modifying potential. Understanding the interplay between cytokine signaling and immune cell dysfunction is crucial for developing precision immunotherapies in MPNs.
费城染色体阴性骨髓增殖性肿瘤（Ph-MPNs）是一类克隆性血液系统恶性肿瘤，其特征不仅在于存在JAK2V617F、CALR和MPL等驱动突变，还在于免疫微环境严重失调。慢性炎症和免疫重塑维持恶性造血，并促使疾病从原发性血小板增多症（ET）和真性红细胞增多症（PV）进展为明显的骨髓纤维化（MF）。促炎细胞因子和趋化因子，包括白细胞介素-2（IL-2）、干扰素-α（IFN-α）、白细胞介素-23（IL-23）和肿瘤坏死因子-α（TNF-α），驱动异常的T细胞极化，有利于致病性Th17表型的形成。淋巴细胞亚群分析显示，耗竭的程序性死亡蛋白1（PD-1）T细胞占优势，反映出免疫监视受损。同时，中性粒细胞凋亡的改变导致持续炎症和基质激活。生长调节致癌基因-α（GRO-α，即CXCL1）在ET中升高，但在MF中降低，提示其在疾病生物学中具有亚型特异性作用。促进纤维化的因子，如转化生长因子-β（TGF-β）和白细胞介素-13（IL-13），介导骨髓重塑和巨核细胞扩增，而血管内皮生长因子（VEGF）和其他血管生成因子则增强血管微环境改变，尤其是在PV中。这些免疫病理特征突显了新的治疗靶点。除了抑制JAK外，CXCR1/2拮抗剂、抗TGF-β药物和免疫检查点抑制剂（PD-1/PD-L1阻断）等靶向策略可能具有改善疾病的潜力。了解细胞因子信号传导与免疫细胞功能障碍之间的相互作用对于开发MPNs的精准免疫疗法至关重要。
