Molecular Cancer Medicine Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Discov. 2020 Nov;10(11):1742-1757. doi: 10.1158/2159-8290.CD-20-0026. Epub 2020 Jul 15.
We investigated the role of PRMT5 in myeloproliferative neoplasm (MPN) pathogenesis and aimed to elucidate key PRMT5 targets contributing to MPN maintenance. PRMT5 is overexpressed in primary MPN cells, and PRMT5 inhibition potently reduced MPN cell proliferation . PRMT5 inhibition was efficacious at reversing elevated hematocrit, leukocytosis, and splenomegaly in a model of JAK2 polycythemia vera and leukocyte and platelet counts, hepatosplenomegaly, and fibrosis in the MPL model of myelofibrosis. Dual targeting of JAK and PRMT5 was superior to JAK or PRMT5 inhibitor monotherapy, further decreasing elevated counts and extramedullary hematopoiesis PRMT5 inhibition reduced expression of E2F targets and altered the methylation status of E2F1 leading to attenuated DNA damage repair, cell-cycle arrest, and increased apoptosis. Our data link PRMT5 to E2F1 regulatory function and MPN cell survival and provide a strong mechanistic rationale for clinical trials of PRMT5 inhibitors in MPN. SIGNIFICANCE: Expression of PRMT5 and E2F targets is increased in JAK2 MPN. Pharmacologic inhibition of PRMT5 alters the methylation status of E2F1 and shows efficacy in JAK2/MPL MPN models and primary samples. PRMT5 represents a potential novel therapeutic target for MPN, which is now being clinically evaluated..
我们研究了 PRMT5 在骨髓增殖性肿瘤（MPN）发病机制中的作用，并旨在阐明有助于 MPN 维持的关键 PRMT5 靶标。PRMT5 在原发性 MPN 细胞中过度表达，PRMT5 抑制可强力降低 MPN 细胞增殖。PRMT5 抑制在 JAK2 真性红细胞增多症和 MPL 骨髓纤维化模型中有效逆转升高的血细胞比容、白细胞增多和脾肿大，以及白细胞和血小板计数、肝脾肿大和纤维化。JAK 和 PRMT5 的双重靶向优于 JAK 或 PRMT5 抑制剂单药治疗，进一步降低升高的计数和骨髓外造血。PRMT5 抑制降低了 E2F 靶标的表达，并改变了 E2F1 的甲基化状态，导致减弱的 DNA 损伤修复、细胞周期停滞和增加的细胞凋亡。我们的数据将 PRMT5 与 E2F1 调节功能和 MPN 细胞存活联系起来，并为 PRMT5 抑制剂在 MPN 中的临床试验提供了强有力的机制依据。意义：PRMT5 和 E2F 靶标的表达在 JAK2 MPN 中增加。PRMT5 的药理学抑制改变了 E2F1 的甲基化状态，并在 JAK2/MPL MPN 模型和原发性样本中显示出疗效。PRMT5 代表了 MPN 的一个潜在的新的治疗靶点，目前正在进行临床评估。
