Lysyl oxidase inhibition in primary myelofibrosis: A renewed strategy.
Lysyl oxidase inhibition in primary myelofibrosis: A renewed strategy.
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DOI：
10.46439/stemcell.1.005
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Ravid K
中科院分区：
文献类型：
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作者：
Piasecki A;Leiva O;Ravid K
原发性骨髓纤维化（PMF）是一种骨髓增生性肿瘤（MPN），预示着预后不良且治疗选择有限。 PMF 通常由调节 JAK-STAT 信号通路的三个基因之一的克隆突变驱动，导致该信号通路过度激活以及巨核细胞 (MK) 及其前体细胞过度增殖。 PMF 会出现使人衰弱的症状，例如脾肿大和体重减轻。少数可用的 PMF 治疗方法包括 JAK2 抑制剂鲁索替尼 (ruxolitinib)，它会引起副作用，而且并不总是有效。细胞外基质（ECM）和骨髓（BM）微环境可能在PMF的发病机制中发挥重要作用。赖氨酰氧化酶 (LOX) 是一种通过促进胶原蛋白和弹性蛋白纤维交联在 ECM 中发挥关键作用的酶，已被证明在 PMF 小鼠和 PMF 患者的 MK 中表达上调，表明其在 BM 纤维化进展中的作用。最近，LOX 已被确定为 PMF 的潜在新型治疗靶点，新型小分子 LOX 抑制剂 PXS-LOX_1 和 PXS-LOX_2 的开发在临床前研究中显示出减缓 PMF 进展的希望。鉴于这些抑制剂表现出通过 LOX 抑制来靶向 ECM 失调的能力，因此它们有望作为 PMF 未被充分认识的方面的治疗剂。
Primary myelofibrosis (PMF) is a type of myeloproliferative neoplasm (MPN) that portends a poor prognosis and has limited options for treatment. PMF is often driven by clonal mutations in one of three genes that regulate the JAK-STAT signaling pathway, leading to hyperactivation of this signaling pathway and over-proliferation of megakaryocytes (MKs) and their precursors. PMF presents with debilitating symptoms such as splenomegaly and weight loss. The few available treatments for PMF include a JAK2 inhibitor, ruxolitinib, which causes side effects and is not always effective. The extracellular matrix (ECM) and bone marrow (BM) microenvironment may play an important role in the pathogenesis of PMF. Lysyl oxidase (LOX), an enzyme that plays a key role in the ECM by facilitating the cross-linking of collagen and elastin fibers, has been shown to be upregulated in MKs of PMF mice and in PMF patients, suggesting its role in the progression of BM fibrosis. Recently, LOX has been identified as a potential novel therapeutic target for PMF and the development of new small molecule LOX inhibitors, PXS-LOX_1 and PXS-LOX_2, has shown some promise in slowing the progression of PMF in pre-clinical studies. Given that these inhibitors displayed an ability to target the dysregulation of the ECM via LOX inhibition, they show promise as therapeutic agents for an underappreciated aspect of PMF.