Departments of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA.
Curr Opin Hematol. 2018 Jul;25(4):266-272. doi: 10.1097/MOH.0000000000000428.
Hematopoietic stem cells (HSCs) produce mature blood cells throughout lifetime. Natural genetic diversity offers an important yet largely untapped reservoir for deciphering regulatory mechanisms of HSCs and hematopoiesis. In this review, we explore the role of latexin, identified by natural variation, in regulating homeostatic and stress hematopoiesis, unravel the underlying signaling pathways, and propose its therapeutic implication.
Latexin acts endogenously in HSCs to negatively regulate their population size by enhancing apoptosis and by decreasing self-renewal. Deletion of latexin in vivo increases HSC repopulation capacity and survival, expands the entire hematopoietic system, and mitigates myelosuppression. Latexin inactivation downregulates thrombospondin 1 (Thbs1). It inhibits nuclear translocation of ribosomal protein subunit 3 (Rps3), a novel latexin-binding protein, and sensitizes hematopoietic cells to radiation-induced cell death. However, how latexin-Rps3 pathway regulates Thbs1 transcription is unclear. Latexin is downregulated in cancer cells because of promoter hypermethylation, but latexin-depleted mice do not inherently develop hematologic malignancies even with aging. The mechanism of action of latexin in tumorigenesis remains largely unknown.
Understanding how latexin regulates HSC survival, self-renewal, and stress response will advance our knowledge of HSC biology. It will facilitate the development of a novel therapeutic strategy for hematopoietic regeneration and cancer treatment.
造血干细胞（HSCs）在整个生命周期中产生成熟的血细胞。天然遗传多样性为解析 HSCs 和造血的调控机制提供了一个重要但尚未充分开发的资源。在这篇综述中，我们探讨了由自然变异所识别的 latexin 在调节稳态和应激造血中的作用，揭示了其潜在的信号通路，并提出了其治疗意义。
内源性 latexin 在 HSCs 中起作用，通过增强凋亡和减少自我更新来负调控其群体大小。体内缺失 latexin 会增加 HSC 重编程能力和存活率，扩大整个造血系统，并减轻骨髓抑制。Latexin 失活会下调血小板反应蛋白 1（Thbs1）。它抑制核糖体蛋白亚基 3（Rps3）的核易位，Rps3 是一种新型的 latexin 结合蛋白，使造血细胞对辐射诱导的细胞死亡敏感。然而，latexin-Rps3 途径如何调节 Thbs1 转录尚不清楚。由于启动子超甲基化，latexin 在癌细胞中下调，但即使随着年龄的增长，latexin 耗尽的小鼠也不会固有地发展出血液系统恶性肿瘤。latexin 在肿瘤发生中的作用机制在很大程度上仍不清楚。
了解 latexin 如何调节 HSC 的存活、自我更新和应激反应将增进我们对 HSC 生物学的认识。它将促进造血再生和癌症治疗的新治疗策略的发展。
