Beyond nuclear export: chromatin-bound XPO1/CRM1 as a transcriptional scaffold

Area of Science:

• Molecular Biology
• Cancer Biology
• Epigenetics

Background:

• Exportin-1 (XPO1/CRM1) is primarily known as a nuclear export receptor.
• XPO1 is emerging as a therapeutic target in acute myeloid leukemia (AML).
• Recent findings show XPO1 localizes to chromatin at active regulatory regions, including HOX clusters and the MEIS1 locus in AML.

Purpose of the Study:

• To reframe the role of XPO1 from a nuclear export receptor to a chromatin-associated interaction hub.
• To provide a framework for understanding transcriptionally addicted AML subtypes.
• To highlight therapeutic opportunities targeting chromatin-associated XPO1 functions in AML.

Main Methods:

• The study is a perspective piece, synthesizing existing evidence and proposing a new model.
• It integrates findings on XPO1 localization, interactions with leukemia drivers (NUP fusions, NPM1c), and chromatin organization.
• The perspective discusses the implications of XPO1's role in liquid-liquid phase separation (LLPS) and transcriptional regulation.

Main Results:

• A
• pre-bound XPO1 platform
• model is supported, where leukemia drivers recruit XPO1 to specific chromatin loci.
• XPO1's dual engagement stabilizes locus-restricted assemblies and promotes LLPS-linked condensate formation.
• Aberrant HOX/MEIS-driven transcriptional programs in AML are sustained by these XPO1-mediated assemblies.

Conclusions:

• XPO1 functions as a chromatin-associated interaction hub in certain AML subtypes.
• This interaction is critical for sustaining aberrant HOX/MEIS transcriptional programs.
• Targeting chromatin-associated XPO1 offers a potential therapeutic strategy for HOX/MEIS-driven AML.