On August 26, teams led by Professor Hou Yu from the College of Basic Medical Sciences, Professor Guo Zufeng from the College of Pharmacy, and Professor Wang Li from the Department of Hematology of the First Affiliated Hospital of Chongqing Medical University jointly published a research article entitled Inhibition of nucleoporin 214 depletes leukemia stem cells by promoting heme catabolism and lipid peroxidation in the renowned international journal Blood.
Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy. Despite continuous advances in therapeutic strategies in recent years, more than 70% of patients die from the disease within five years after diagnosis. Leukemia stem cells (LSCs) are the root cause of AML initiation, relapse and chemoresistance. Efficient elimination of LSCs holds the key to curing AML, yet targeted intervention strategies against LSCs remain very limited. Nucleoporins (NUPs) comprise a family of approximately 30 conserved proteins that assemble into nuclear pore complexes (NPCs) to mediate nucleocytoplasmic transport. Recent studies have identified nucleoporins as promising therapeutic targets in multiple solid malignancies; however, nucleoporin targets in AML, especially in LSCs, remain poorly defined. In addition, gene fusion mutations of nucleoporins are frequently detected in AML patients, further indicating the vital role of nucleoporins in leukemogenesis. It is therefore urgent to investigate their functions and targetability in LSCs.
In this study, through systematic screening of the nucleoporin family, the research team found that NUP214 is specifically highly expressed in LSCs, and its expression level is strongly correlated with poor prognosis in AML patients. In multiple AML mouse models driven by MLL-AF9 and HOXA9/MEIS1, as well as patient-derived xenograft (PDX) models, NUP214 deletion or knockdown effectively impairs LSC maintenance and markedly delays malignant progression of AML. Notably, heterozygous NUP214 knockout (haploinsufficiency) exerts minimal effects on normal hematopoietic stem cells while efficiently eradicating LSCs, suggesting a selective therapeutic window for NUP214 targeting and providing a theoretical basis for the clinical translation of NUP214-directed therapies.
Mechanistically, the team demonstrated that NUP214 does not merely function as a structural component of nuclear pore complexes. Instead, it translocates from the nuclear envelope into the nucleoplasm in LSCs. Once inside the nucleus, NUP214 directly binds to the transcriptional coactivator Sub1 and blocks Sub1-mediated recruitment of RNA polymerase II, thereby suppressing transcription of the pro-ferroptotic genes HMOX1 and ALOX15. This non-canonical function reveals a novel role of NUP214 as a transcriptional repressor: it protects LSCs from ferroptosis by actively inhibiting heme catabolism and lipid peroxidation. Interestingly, the nucleoplasmic translocation of NUP214 is LSC-specific. In normal hematopoietic stem cells, NUP214 is predominantly localized at the nuclear envelope, which further accounts for the feasibility of selective intervention.
To address the bottleneck of lacking NUP214 inhibitors, the research team combined virtual screening and experimental screening and successfully developed a small-molecule degrader 0449-b targeting NUP214. 0449-b recruits NUP214 to the Cullin5-Rbx2 E3 ubiquitin ligase complex, induces its NEDDylation modification, and triggers its degradation via the proteasome pathway. This compound potently degrades NUP214 protein, effectively induces ferroptosis in LSCs both in vitro and in vivo, and exhibits negligible toxicity to normal hematopoietic stem cells within the effective dose range. In PDX models, monotherapy with 0449-b significantly suppresses AML progression and eliminates LSCs, demonstrating a favorable therapeutic window.
In summary, this study establishes NUP214 as a critical dependency target of LSCs, uncovers the non-canonical function of nucleoporins in transcriptional regulation, and provides a small-molecule degrader of NUP214, offering a new strategy for precision intervention of AML.
Professors Hou Yu from the College of Basic Medical Sciences, Guo Zufeng from the Colleg of Pharmacy, and Wang Li from the Department of Hematology, the First Affiliated Hospital of Chongqing Medical University, are co-corresponding authors of this paper. Associate Professor Chen Zhe from the School of Basic Medical Sciences, PhD candidates Wu Feng and Zhang Wei, and Postdoctoral Fellow Li Yan are co-first authors. This research was supported by the National Natural Science Foundation of China, the New Chongqing Young Innovative Talents Program, the Natural Science Foundation of Chongqing, and other grants.
(Translated by AI)
