XPO1-dependency of DEK::NUP214 leukemia

Area of Science:

• Oncology
• Molecular Biology
• Hematology

Background:

• The nuclear export protein XPO1 interacts with NUP214, contributing to SET::NUP214 acute myeloid leukemia (AML) pathogenesis.
• DEK::NUP214 (DN) defines a distinct AML entity, whose dependency on XPO1 was previously uncharacterized.

Purpose of the Study:

• To evaluate the dependency of DEK::NUP214 (DN) AML on XPO1.
• To investigate the therapeutic potential of XPO1 inhibition in DN-AML models.

Main Methods:

• Utilized human AML cell lines (FKH-1) and primary cells.
• Employed the selective nuclear export inhibitor eltanexor.
• Assessed XPO1 expression, protein co-localization, apoptosis, cell cycle arrest, and chromatin binding.
• Evaluated a patient-derived DN-AML xenograft model.

Main Results:

• XPO1 deletion and eltanexor treatment induced apoptosis and cell cycle arrest in DN-positive cells.
• XPO1 inhibition disrupted XPO1 and DN co-localization at chromatin.
• Loss of chromatin binding led to downregulation of DN target genes involved in cell cycle and self-renewal.
• Eltanexor treatment significantly delayed leukemia development in a xenograft model.

Conclusions:

• XPO1 stabilizes the DEK::NUP214 fusion protein at chromatin, activating its oncogenic gene signature.
• Targeting XPO1 with eltanexor demonstrates successful in vivo treatment of DN-AML.
• XPO1 is established as a viable molecular target for DEK::NUP214 AML therapy.