Oncotarget

Research Papers:

Targeted CRM1-inhibition perturbs leukemogenic NUP214 fusion proteins and exerts anti-cancer effects in leukemia cell lines with NUP214 rearrangements

Adélia Mendes, Ramona Jühlen, Valérie Martinelli and Birthe Fahrenkrog _

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Oncotarget. 2020; 11:3371-3386. https://doi.org/10.18632/oncotarget.27711

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Abstract

Adélia Mendes1, Ramona Jühlen1,2, Valérie Martinelli1 and Birthe Fahrenkrog1

1 Institute of Molecular Biology and Medicine, Université Libre de Bruxelles, Charleroi 6041, Belgium

2 Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen 52074, Germany

Correspondence to:

Birthe Fahrenkrog,email: bfahrenk@ulb.ac.be

Keywords: CRM1; NUP214; leukemia; nuclear export; nucleoporin

Received: May 23, 2020     Accepted: August 01, 2020     Published: September 08, 2020

ABSTRACT

Chromosomal translocations fusing the locus of nucleoporin NUP214 each with the proto-oncogenes SET and DEK 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.


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