Ribosome biogenesis and its regulation by the exportin, CSE1L, are selective 4 dependencies in childhood and young adult acute myeloid leukemia

ABSTRACT: Nuclear transport receptors, termed importins and exportins, regulate protein transport between the nucleus and cytoplasm through the nuclear pore. Although genetic alterations in the nuclear pore complex are more common in childhood, adolescent and young adult (AYA) AML, nucleocytoplasmic transport has not been studied extensively in childhood/AYA AML. We compared the expression of genes associated with nucleocytoplasmic transport in young and older AML patients and identified enrichment of nucleocytoplasmic transport pathways in childhood/AYA AML. Of the nucleocytoplasmic genes, CSE1L was the top expressed exportin in young AML patients. CSE1L depletion reduced growth, viability and clonogenicity in young (<40 years) AML cell lines and patient samples but spared normal hematopoietic cells. Mechanistically, CSE1L contributed to leukemogenesis by participating in ribosome biogenesis and nuclear export of the pre-ribosomal large subunit (pre-60S). Ribosome biogenesis pathways were the most abundantly expressed gene sets in young AML patients and young primary AML samples demonstrated enhanced rates of ribosome biogenesis and increased sensitivity to ribosome biogenesis inhibitors, compared to older AML samples. Our findings reinforce growing evidence that childhood/AYA AML is a fundamentally different disease to AML in older adults, and is driven by different biologic processes. Through inhibition of CSE1L, or the downstream process it regulates, ribosome biogenesis, we have identified a novel way to target leukemogenesis in childhood/AYA AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290584 | GEO | 2026/02/26

REPOSITORIES: GEO