CSE1L enrichment in pediatric and young adult acute myeloid leukemia reveals a ribosomal export dependency

Proteins shuttle between the nucleus and cytoplasm through the nuclear pore and via nuclear transport receptors, termed importins and exportins. Although genetic alterations involving nucleoporins are enriched in pediatric, adolescent, and young adult (AYA) acute myeloid leukemia (AML), nucleocytoplasmic transport has not been extensively studied in this disease. We discover that genes encoding nucleocytoplasmic transport pathway components (Kyoto Encyclopedia of Genes and Genomes [KEGG]: hsa03013) are enriched in AML cells from younger patients (≤40 years). Within this pathway, CSE1L is the highest expressed exportin in pediatric/AYA AML and shows minimal expression in hematopoietic stem cells (HSCs). CSE1L depletion reduces leukemic cell growth, proliferation, and clonogenic capacity, targeting leukemia stem cells while sparing normal HSCs. Mechanistically, we identify a novel Ran-GTP-dependent role for CSE1L in regulating pre-60S ribosomal subunit export in AML. Collectively, these data identify nucleocytoplasmic transport and ribosomal subunit export as enriched dependencies in pediatric/AYA AML and establish CSE1L-mediated export as a leukemic vulnerability.