Involvement of PML-I in reformation of PML nuclear bodies in acute promyelocytic leukemia cells by leptomycin B.
Involvement of PML-I in reformation of PML nuclear bodies in acute promyelocytic leukemia cells by leptomycin B.
复制标题
DOI：
10.1016/j.taap.2019.114775
复制
发表时间：
2019-12
影响因子：
3.8
通讯作者：
Chao Wang;L. Su;Y. Shao;Wei Zhong Chen;Na Bu;Rui Hao;L. Ma;Liaqat Hussain;X. Lu;Qian Qian Wang-Qian;Hua Naranmandura
中科院分区：
文献类型：
--
作者：
Chao Wang;L. Su;Y. Shao;Wei Zhong Chen;Na Bu;Rui Hao;L. Ma;Liaqat Hussain;X. Lu;Qian Qian Wang-Qian;Hua Naranmandura
急性早幼粒细胞白血病（Acute promyelocytic leukemia，APL）是一种以t（15;17）染色体相互易位为特征的白血病，其特征是：t（15;17）染色体易位导致PML-RARα融合蛋白表达，使正常的PML核小体（PML-NBs）破坏成微小斑点状，从而丧失其原有功能。砷对APL患者PML-NBs的改造被认为是APL治疗的重要步骤之一。瘦霉素B（LMB）是一种核输出抑制剂，常用于抑制蛋白质从核输出到胞质。在本研究中，我们发现LMB可以诱导白血病NB 4细胞以及APL患者的原始细胞中PML-NB的重组，这意味着核穿梭蛋白可能参与PML-NB的重组。在此，我们进一步发现，当内源性PML基因被敲除时，LMB完全丧失了诱导PML-NB重组的能力，表明内源性PML蛋白可能参与PML-NB的重组。更有趣的是，在所有PML亚型中（即，7种异构体），仅在LMB处理后PML-RARα与PML-I共转染时观察到PML-NB的重组。同样，PML-I的核输出信号（内斯）缺失也能改革PML-NB，提示核内内源性PML-I的蛋白水平对PML-RARα融合蛋白干扰的PML-NB的改造具有重要意义。此外，LMB与iAsIIIon对PML-RARα融合蛋白的降解具有协同作用，有望为APL的临床治疗提供新的思路。
Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation between chromosomes 15 and 17, t(15;17), resulting in the expression of PML-RARα fusion protein, which disrupts the normal PML nuclear bodies (PML-NBs) to micro-speckled pattern, leading to loss of their original functions. Moreover, reformation of PML-NBs in APL by arsenic is considered as one of the important step for APL treatment. Leptomycin B (LMB), a nuclear export inhibitor, is commonly used to inhibit the proteins exporting from the nucleus to the cytoplasm. In the present study, we found that LMB could induce the reformation of PML-NBs in leukemia NB4 cells as well as in APL blast cells from the patients, implying that nuclear shuttle proteins might be involved in the reformation of PML-NBs. Herein, we further found that LMB totally lost the ability to induce PML-NBs reformation when the endogenous PML gene was knocked out, indicating that endogenous PML protein is probably involved in the reformation of PML-NBs. More interestingly, among all PML isoforms (i.e., seven isoforms), reformation of PML-NBs was only observed when co-transfection of PML-RARα with PML-I after LMB treatment. Similarly, deletion of nuclear export signal (NES) of PML-I could also reform PML-NBs, suggesting that the protein level of endogenous PML-I in nucleus is important for the reformation of PML-NBs that interfered by PML-RARα fusion protein. Additionally, LMB has synergistic effect with iAsIIIon enhancing PML-RARα fusion protein degradation, and it might provide new insight into APL treatment at clinical level in the near future.