Preclinical study demonstrates that targeted NUP214 degradation induces ferroptosis in leukemia stem cells, highlighting a novel therapeutic vulnerability in acute myeloid leukemia.
Key Points
To determine the functional role of wild-type nucleoporin 214 (NUP214) in leukemia stem cell maintenance and evaluate targeted NUP214 degradation as a therapeutic strategy for acute myeloid leukemia.
Screened nucleoporin family genes in leukemia stem cells (LSCs) to identify key fitness drivers and characterized downstream metabolic and transcriptional pathways.
Investigated the mechanism of NUP214 in the nucleoplasm, focusing on Sub1-mediated RNA polymerase II recruitment to pro-ferroptotic gene targets.
Developed a small-molecule degrader (0449-b) that recruits NUP214 to the Cullin5-Rbx2 E3 ligase complex and evaluated its efficacy and toxicity in vivo.
NUP214 is frequently overexpressed in LSCs, where it represses HMOX1 and ALOX15 transcription by blocking Sub1-dependent RNA polymerase II recruitment.
Inhibition or loss of NUP214 triggers excessive heme catabolism, Fe²⁺ accumulation, and lethal lipid peroxidation, driving selective ferroptotic death in LSCs.
The selective degrader 0449-b mediated proteasomal breakdown of NUP214, demonstrating potent in vivo anti-leukemic activity while sparing normal hematopoietic stem cells.