PDF(Pubmed)
Abstract：
The noncanonical NF-κB pathway is involved in lymphoid organ development, B-cell maturation, and cytokine production. However, new research has demonstrated that this pathway is also key for the orderly and sequential maturation of myeloid cells, including neutrophils and eosinophils. When this pathway is disrupted or constitutively activated, aberrations in hematopoietic stem and progenitor cell survival and proliferation, as well as subsequent granulopoiesis and eosinophilopoiesis, are affected. Disturbance of such a coordinated and delicate process can manifest in devastating clinical disease, including acute and chronic myeloid leukemias, preleukemic processes such as myelodysplastic syndrome, or hyperinflammatory conditions like hypereosinophilic syndrome. In this review, we discuss the molecular machinery within the noncanonical NF-κB pathway, crosstalk with the canonical NF-κB pathway, murine models of noncanonical signaling, and how aberrations in this pathway manifest in leukemic or hyperinflammatory disease with a focus on hypereosinophilic syndrome. Potential and promising drug therapies will also be discussed, emphasizing the noncanonical NF-κB pathway as a potential target for improved treatment for patients with leukemia or idiopathic hypereosinophilic syndrome. The hope is that review of such mechanisms and treatments may eventually result in findings that aid physicians in rapidly diagnosing and more accurately classifying patients with such complex and overlapping hematopoietic diseases.
摘要：
非经典NF-κB通路参与淋巴器官发育，B细胞成熟,和细胞因子的产生。然而,新的研究表明，该途径也是骨髓细胞有序和连续成熟的关键，包括嗜中性粒细胞和嗜酸性粒细胞。当这个途径被破坏或组成性激活时，造血干细胞和祖细胞（HSPC）存活和增殖的畸变，以及随后的粒细胞生成和嗜酸性粒细胞生成受到影响。这种协调和微妙的过程的紊乱可以表现为破坏性的临床疾病，包括急性和慢性髓性白血病（AML和CML，分别)，白血病前期如骨髓增生异常综合征(MDS)或嗜酸性粒细胞增多综合征(HES).在这次审查中,我们将讨论非规范NF-κB途径中的分子机制，与经典NF-κB通路的串扰，非规范信号的鼠模型，以及该途径的畸变在白血病或高炎症性疾病中如何表现，重点是HES。还将讨论潜在和有前途的药物疗法，强调非经典NF-κB途径是改善白血病或特发性HES患者治疗的潜在靶标。希望对这种机制和治疗方法的审查最终可能会导致发现，帮助医生快速诊断并更准确地对患有这种复杂和重叠的造血疾病的患者进行分类。
