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

XPO1/CRM1 (also known as Exportin-1) is best known as a RanGTP-dependent nuclear export receptor and has been explored as a therapeutic target in various diseases, including acute myeloid leukemia (AML). Emerging evidence, however, indicates that XPO1 is also detectable on chromatin at active regulatory regions, including the HOX clusters and the MEIS1 locus-key transcriptional nodes in multiple AML subtypes. Recent studies support a "pre-bound XPO1 platform" model in which genetically diverse leukemia drivers, such as nucleoporin (NUP98/NUP214) fusions and mutant NPM1 (NPM1c), are recruited to these loci via phenylalanine-glycine (FG) repeat-XPO1 or nuclear export signal (NES)-XPO1 interactions, coupled with partner-encoded chromatin contacts. This dual engagement may stabilize locus-restricted assemblies and lower the threshold for liquid-liquid phase separation (LLPS)-linked condensate formation that sustains aberrant HOX/MEIS-driven transcriptional programs. By reframing XPO1 from a nuclear export receptor to a chromatin-associated interaction hub, this perspective provides a framework for understanding transcriptionally addicted AML subtypes and highlights opportunities to selectively target chromatin-associated XPO1 functions in HOX/MEIS-driven AML.