Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition.
Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition.
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DOI：
10.1038/nm.3995
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发表时间：
2015-12
期刊：
影响因子：
82.9
通讯作者：
Crispino JD
中科院分区：
文献类型：
--
作者：
Wen QJ;Yang Q;Goldenson B;Malinge S;Lasho T;Schneider RK;Breyfogle LJ;Schultz R;Gilles L;Koppikar P;Abdel-Wahab O;Pardanani A;Stein B;Gurbuxani S;Mullally A;Levine RL;Tefferi A;Crispino JD
原发性骨髓纤维化（PMF）的特征是骨髓纤维化、骨髓增生、髓外造血、脾肿大和白血病进展。此外，患者的骨髓和脾脏充满了非典型巨核细胞，这些细胞被认为通过释放包括TGF-β在内的细胞因子而促成纤维化。虽然JAK抑制剂ruxolitinib提供症状缓解，但它不会减少突变等位基因负担或显著逆转纤维化。在这里，我们通过药理学和遗传学研究表明，除了JAK 2，极光激酶A（AURKA）是PMF的一个新的治疗靶点。MLN 8237是一种选择性AURKA抑制剂，可促进PMF巨核细胞的多倍化和分化，并在体内显示出强效抗纤维化和抗肿瘤活性。我们还发现，AURKA的一个等位基因的丢失足以改善体内纤维化和其他PMF表型。我们的数据表明，巨核细胞是纤维化的驱动因素，用AURKA抑制剂靶向它们将在PMF中提供治疗益处。
Primary myelofibrosis (PMF) is characterized by bone marrow fibrosis, myeloproliferation, extramedullary hematopoiesis, splenomegaly and leukemic progression. Moreover, the bone marrow and spleen of patients are full of atypical megakaryocytes that are postulated to contribute to fibrosis through the release of cytokines including TGF-β. Although the JAK inhibitor ruxolitinib provides symptomatic relief, it does not reduce the mutant allele burden or significantly reverse fibrosis. Here we show through pharmacologic and genetic studies that, apart from JAK2, Aurora kinase A (AURKA) is a novel therapeutic target in PMF. MLN8237, a selective AURKA inhibitor promoted polyploidization and differentiation of PMF megakaryocytes and displayed potent anti-fibrotic and anti-tumor activity in vivo. We also reveal that loss of one allele of AURKA is sufficient to ameliorate fibrosis and other PMF phenotypes in vivo. Our data suggest that megakaryocytes are drivers of fibrosis and that targeting them with AURKA inhibitors will provide therapeutic benefit in PMF.