Mendes Adélia, Jühlen Ramona, Martinelli Valérie, Fahrenkrog Birthe
Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, Charleroi 6041, Belgium.
Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen 52074, Germany.
Oncotarget. 2020 Sep 8;11(36):3371-3386. doi: 10.18632/oncotarget.27711.
Chromosomal translocations fusing the locus of nucleoporin each with the proto-oncogenes and are recurrent in, largely intractable, acute leukemias. The molecular basis underlying the pathogenesis of SET-NUP214 and DEK-NUP214 are still poorly understood, but both chimeras inhibit protein nuclear export mediated by the β-karyopherin CRM1. In this report, we show that SET-NUP214 and DEK-NUP214 both disturb the localization of proteins essential for nucleocytoplasmic transport, in particular for CRM1-mediated protein export. Endogenous and exogenous SET-NUP214 and DEK-NUP214 form nuclear bodies. These nuclear bodies disperse upon targeted inhibition of CRM1 and the two fusion proteins re-localize throughout the nucleoplasm. Moreover, SET-NUP214 and DEK-NUP214 nuclear bodies reestablish shortly after removal of CRM1 inhibitors. Likewise, cell viability, metabolism, and proliferation of leukemia cell lines harboring SET-NUP214 and DEK-NUP214 are compromised by CRM1 inhibition, which is even sustained after clearance from CRM1 antagonists. Our results indicate CRM1 as a possible therapeutic target in NUP214-related leukemia. This is especially important, since no specific or targeted treatment options for NUP214 driven leukemia are available yet.
将核孔蛋白基因座与原癌基因和融合的染色体易位在很大程度上难以治疗的急性白血病中经常出现。SET-NUP214和DEK-NUP214发病机制的分子基础仍知之甚少，但这两种嵌合体均抑制由β-核转运蛋白CRM1介导的蛋白质核输出。在本报告中，我们表明SET-NUP214和DEK-NUP214均干扰核质运输所必需的蛋白质的定位，特别是CRM1介导的蛋白质输出。内源性和外源性SET-NUP214和DEK-NUP214形成核体。在靶向抑制CRM1后，这些核体分散，并且两种融合蛋白重新定位到整个核质中。此外，在去除CRM1抑制剂后不久，SET-NUP214和DEK-NUP214核体重新形成。同样，携带SET-NUP214和DEK-NUP214的白血病细胞系的细胞活力、代谢和增殖受到CRM1抑制的影响，即使在从CRM1拮抗剂清除后这种影响仍持续存在。我们的结果表明CRM1可能是NUP214相关白血病的治疗靶点。这一点尤为重要，因为目前尚无针对NUP214驱动的白血病的特异性或靶向治疗方案。
