Panobinostat (LBH589)-induced acetylation of tubulin impairs megakaryocyte maturation and platelet formation.
Panobinostat (LBH589)-induced acetylation of tubulin impairs megakaryocyte maturation and platelet formation.
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DOI：
10.1016/j.exphem.2012.02.004
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发表时间：
2012-07
影响因子：
2.6
通讯作者：
Hoffman, Ronald
中科院分区：
文献类型：
--
作者：
Iancu-Rubin, Camelia;Gajzer, David;Mosoyan, Goar;Feller, Faye;Mascarenhas, John;Hoffman, Ronald
药物引起的血小板减少症通常是由于正常巨核细胞生成失调所致。在这项研究中，我们研究了与使用帕比司他 (LBH589) 相关的血小板减少症的机制，帕比诺司他 (LBH589) 是一种组蛋白脱乙酰酶抑制剂 (HDACi)，具有良好的抗癌活性。通过利用离体系统测试 LBH589 对巨核细胞生成的细胞和分子方面的影响，其中成熟的巨核细胞 (MK) 和血小板由人原代 CD34+ 细胞产生。我们证明LBH589不影响MK增殖或谱系定型，但抑制MK成熟和血小板形成。尽管 LBH589 对初级 MK 的处理会导致组蛋白过度乙酰化，但它不会干扰在巨核细胞生成过程中发挥重要作用的基因的表达。相反，我们发现 LBH589 诱导微管蛋白的翻译后修饰，微管蛋白是一种非组蛋白，是微管 (MT) 细胞骨架的主要组成部分。然后，我们证明 LBH589 治疗诱导微管蛋白过度乙酰化，并改变 MK 适当成熟和血小板形成所需的 MT 动力学和组织。这项研究为 LBH589 诱导的血小板减少症的机制提供了新的见解，并为使用微管蛋白作为选择性 HDACi 疗法的靶标来治疗骨髓增生性肿瘤患者的血小板增多症提供了理论依据。
Drug-induced thrombocytopenia often results from dysregulation of normal megakaryocytopoiesis. In this study, we investigated the mechanisms responsible for thrombocytopenia associated with the use of Panobinostat (LBH589), a histone deacetylase inhibitor (HDACi) with promising anti-cancer activities. The effects of LBH589 were tested on the cellular and molecular aspects of megakaryocytopoiesis by utilizing an ex vivo system in which mature megakaryocytes (MK) and platelets were generated from human primary CD34+ cells. We demonstrated that LBH589 did not affect MK proliferation or lineage commitment but inhibited MK maturation and platelet formation. Although LBH589 treatment of primary MK resulted in hyperacetylation of histones, it did not interfere with the expression of genes that play important roles during megakaryocytopoiesis. Instead, we found that LBH589 induced posttranslational modifications of tubulin, a non-histone protein that is the major component of the microtubule (MT) cytoskeleton. We then demonstrated that LBH589 treatment induced hyperacetylation of tubulin and alteration of MT dynamics and organization required for proper MK maturation and platelet formation. This study provides new insights into the mechanisms underlying LBH589-induced thrombocytopenia and provides a rationale for using tubulin as a target for selective HDACi therapies to treat thrombocytosis in patients with myeloproliferative neoplasms.
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