Disulfidptosis in pediatric AML: a multi-omics approach to risk stratification and potential therapeutic strategy.

BACKGROUND

The evolving molecular portrait of acute myeloid leukemia (AML) has exposed previously unrecognized cell death programs that fuel disease progression and treatment resistance-uncovering untapped therapeutic potential. Recent work has uncovered disulfidptosis-a novel form of programmed cell death (PDC) triggered by glucose deprivation in SLC7A11-high AML cells-as a potential therapeutic vulnerability. However, disulfidptosis in pediatric AML (pAML) remains largely unexplored, with no comprehensive studies assessing its biological significance or clinical prognostic value.

METHOD: Here, we systematically characterize disulfidptosis in pediatric AML through multi-omics integration. Using ssGSEA, we quantified PDC patterns across bulk and single-cell transcriptomes, revealing distinct molecular subtypes via unsupervised clustering. Machine learning deciphered the biological networks underlying disulfidptosis, while in vitro experiments were performed to further validate.

RESULTS

In this study, we demonstrated that elevated disulfidptosis scores were associated with poor prognosis and a hypermetabolic state. Notably, patients carrying different driver mutations exhibited distinct levels of disulfidptosis susceptibility. Through in vitro experiments utilizing both cell lines and primary patient-derived cells, we found that elevated expression of SLC7A11, a key regulator of disulfidptosis, correlated with chemoresistance. Furthermore, disulfidptosis signatures effectively stratified risk subgroups in pAML, revealing a novel subtype, DSP3, characterized by prominent disulfidptosis features, an immune-desert tumor microenvironment, and an unfavorable prognosis. Additionally, our in vitro experiments identified the GLUT1 inhibitor STF-31 and the mitochondrial-targeted agent darinaparsin as potential therapeutic options for DSP3 patients, and combining with conventional chemotherapy exhibited a synergistic anti-tumor effect.

CONCLUSION

In summary, this study employed multi-omics analysis to examine the characteristics of pAML in the context of disulfidptosis, identifying a novel disulfidptosis-related subtype, aiming to provide new insights for future studies on optimizing traditional regimen based on pAML pathogenesis.