NUP98 Fusion Oncoproteins Promote Aneuploidy by Attenuating the Mitotic Spindle Checkpoint

Valentina Salsi,Francesca Chiavolelli,Cristina Mecucci,Silvia Ferrari,Sebastian Fantini,Vincenzo Zappavigna,Paolo Gorello

doi:10.1158/0008-5472.can-13-0912

Valentina Salsi, Francesca Chiavolelli + Show 5 more

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https://doi.org/10.1158/0008-5472.can-13-0912

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Abstract

NUP98 is a recurrent fusion partner in chromosome translocations that cause acute myelogenous leukemia. NUP98, a nucleoporin, and its interaction partner Rae1, have been implicated in the control of chromosome segregation, but their mechanistic contributions to tumorigenesis have been unclear. Here, we show that expression of NUP98 fusion oncoproteins causes mitotic spindle defects and chromosome missegregation, correlating with the capability of NUP98 fusions to cause premature securin degradation and slippage from an unsatisfied spindle assembly checkpoint (SAC). NUP98 fusions, unlike wild-type NUP98, were found to physically interact with the anaphase promoting complex/cyclosome (APC/C)(Cdc20) and to displace the BubR1 SAC component, suggesting a possible mechanistic basis for their interference with SAC function. In addition, NUP98 oncoproteins displayed a prolonged half-life in cells. We found that NUP98 stability is controlled by a PEST sequence, absent in NUP98 oncoproteins, whose deletion reproduced the aberrant SAC-interfering activity of NUP98 oncoproteins. Together, our findings suggest that NUP98 oncoproteins predispose myeloid cells to oncogenic transformation or malignant progression by promoting whole chromosome instability.

Highlights

NUP98 represents one of the most "promiscuous" [1] partner genes in chromosomal translocations causing acute myelogenous leukemias (AML), as it is involved in the formation of fusion oncoproteins with more than 20 different proteins, among which nine HOX family members [1, 2]
We show in addition that NUP98 oncoproteins have an anomalously prolonged intracellular half-life and that the stability of NUP98 depends on a PEST sequence located within the C-terminal portion that is absent in NUP98 oncoproteins
To verify the effect of NUP98 fusion oncoproteins on chromosome segregation, we exogenously expressed the NUP98-HOXD13, NUP98-LOC348801, and NUP98-hematopoietically expressed homeobox gene (HHEX) fusions in human primary fibroblasts (hPF) and HEK293 human embryonic kidney cells

Summary

Introduction

NUP98 represents one of the most "promiscuous" [1] partner genes in chromosomal translocations causing acute myelogenous leukemias (AML), as it is involved in the formation of fusion oncoproteins with more than 20 different proteins, among which nine HOX family members [1, 2]. HOX genes can participate in oncogenesis through their involvement in chromosomal translocations These lead in some cases to the formation of fusion oncoproteins, composed of the N-terminal part of the NUP98 protein, and usually the homeodomain portion of a HOX protein [1, 2, 5]. NUP98 codes for a nucleoporin, which is involved in the transport of proteins and RNA across the nuclear membrane [6,7,8,9]. The NUP98 protein contains two partially characterized functional domains: a GLFG repeat region, which serves as a nuclear transport

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