Expression of Leukemia-Associated Nup98 Fusion Proteins Generates an Aberrant Nuclear Envelope Phenotype

Abstract

Chromosomal translocations involving the nucleoporin NUP98 have been described in several hematopoietic malignancies, in particular acute myeloid leukemia (AML). In the resulting chimeric proteins, Nup98's N-terminal region is fused to the C-terminal region of about 30 different partners, including homeodomain (HD) transcription factors. While transcriptional targets of distinct Nup98 chimeras related to immortalization are relatively well described, little is known about other potential cellular effects of these fusion proteins. By comparing the sub-nuclear localization of a large number of Nup98 fusions with HD and non-HD partners throughout the cell cycle we found that while all Nup98 chimeras were nuclear during interphase, only Nup98-HD fusion proteins exhibited a characteristic speckled appearance. During mitosis, only Nup98-HD fusions were concentrated on chromosomes. Despite the difference in localization, all tested Nup98 chimera provoked morphological alterations in the nuclear envelope (NE), in particular affecting the nuclear lamina and the lamina-associated polypeptide 2α (LAP2α). Importantly, such aberrations were not only observed in transiently transfected HeLa cells but also in mouse bone marrow cells immortalized by Nup98 fusions and in cells derived from leukemia patients harboring Nup98 fusions. Our findings unravel Nup98 fusion-associated NE alterations that may contribute to leukemogenesis.

<b><i>TMEM18</i></b>: A Novel Prognostic Marker in Acute Myeloid Leukemia

“…NUP98, a mobile nucleoporin, regulates protein import, mRNA export, mitotic spindle assembly, and expression of interferon-γ-inducible genes [27-31]. Chromosomal translocations involving NUP98 have been reported in AML patients [32], where an N-terminal region has been found fused to the C-terminus of about 30 different partners [33]. NUP98 chimera proteins cause alterations in the nuclear envelope and distributions of lamin A/C, lamin B1, and lamina-associated polypeptide 2α [33].…”

“…Chromosomal translocations involving NUP98 have been reported in AML patients [32], where an N-terminal region has been found fused to the C-terminus of about 30 different partners [33]. NUP98 chimera proteins cause alterations in the nuclear envelope and distributions of lamin A/C, lamin B1, and lamina-associated polypeptide 2α [33]. Changes in the expression levels of lamina A and C have been reported [34].…”

The roles of the nuclear pore complex in cellular dysfunction, aging and disease

“…The homeodomain fusions exogenously upregulate HoxA cluster genes, inhibit differentiation, and increase self-renewal [130]. Recently, Nup98 fusion proteins were found to alter nuclear envelope morphology, which further expands the possible mechanisms [131]. Additionally, Nup98 fusions to TopII beta and SETBP1 were shown to displace wild-type Nup98 and subsequently reduce Crm1-dependent nucleocytoplasmic export [132].…”

Bridge-Induced Translocation between NUP145 and TOP2 Yeast Genes Models the Genetic Fusion between the Human Orthologs Associated With Acute Myeloid Leukemia

“…In particular, the amino terminus of Nup98 is known to be involved in the fusions with at least 28 different partners provoking different types of leukemia ( 5 ). In the past, several mouse models of retroviral-introduced artificial fusions have been developed ( 6 , 7 ) and potential therapeutic targets for specific Nup98 fusions-mediated transformation are under studies ( 8 ), but the exact role of the Nup98 chimeras in cell immortalization remains still unclear ( 9 , 10 ). Moreover, previous works were mostly focused on the clinical effects of the chimeric fusion rather than on the genetic etiology of the disease.…”