The pyroptosis-related gene signature predicts prognosis and reveals characterization of the tumor immune microenvironment in acute myeloid leukemia

Abstract

Background: Pyroptosis is a novel inflammatory form of programmed cell death and a prospective target for cancer therapy. Nevertheless, little is known about the association between pyroptosis-related genes (PRGs) and acute myeloid leukemia (AML) prognosis. Herein, we systematically investigated the specific functions and clinical prognostic value of multiple PRGs in AML.Methods: Univariate and LASSO Cox regression analyses based on TCGA and GTEx databases were used to generate the PRG signature, whose predictive efficacy of survival was evaluated using survival analysis, ROC, univariate and multivariate Cox analyses as well as subgroup analysis. The BeatAML cohort was used for data validation. The association between risk score and immune cell infiltration, HLA, immune checkpoints, cancer stem cell (CSC), tumor mutation burden (TMB), and therapeutic drug sensitivity were also analyzed.Results: Six -PRG signatures, namely, CASP3, ELANE, GSDMA, NOD1, PYCARD, and VDR were generated. The high-risk score represented a poorer prognosis and the PRG risk score was also validated as an independent predictor of prognosis. A nomogram including the cytogenetic risk, age, and risk score was constructed for accurate prediction of 1-, 3-, and 5-year survival probabilities. Meanwhile, this risk score was significantly associated with the tumor immune microenvironment (TIME). A high-risk score is characterized by high immune cell infiltration, HLA, and immune checkpoints, as well as low CSC and TMB. In addition, patients with low-risk scores presented significantly lower IC50 values for ATRA, cytarabine, midostaurin, doxorubicin, and etoposide.Conclusion: Our findings might contribute to further understanding of PRGs in the prognosis and development of AML and provide novel and reliable biomarkers for its precise prevention and treatment.

Development of a novel pyroptosis-related LncRNA signature with multiple significance in acute myeloid leukemia

“…Accumulating evidences indicated that chronic inflammation in tumor microenvironment (TME) played a major role in immune invasion, thus contributing to tumorigenesis (Grivennikov et al, 2010;Shin and Brusselle, 2014; Frontiers in Genetics frontiersin.org Lu et al, 2021). In some studies of pyroptosis in AML, TME was found remarkably different between risk groups (He et al, 2022;Shao et al, 2022;Zhou et al, 2022). Pyroptosis, an inflammationdependent form of PCD, was proved to participate in tumor growth and chemosensitivity (Xia et al, 2019), while its mechanisms are complicated.…”

“…The recruitment of inflammatory cells, cytokines and chemokines results in the inflammatory TME which contributes to metastasis and invasion of tumor cells, modulates the anti-tumor immune response and influences the sensitivity to chemotherapeutic drugs. Previous studies suggested the high-risk group of pyroptosis-related signature was enriched in immunosuppressive cells and had lower drug sensitivity to classical chemotherapy ( Pan et al, 2022 ; Shao et al, 2022 ; Zhou et al, 2022 ). In pediatric patients with AML, PRGs were found to predict recurrence ( He et al, 2022 ).…”

“…The researches for the relationship between pyroptosis and tumor may provide some inspirations for clinical treatments. Recent several researches showed pyroptosis-related protein-coding genes could predict prognosis in AML ( He et al, 2022 ; Liu et al, 2022 ; Pan et al, 2022 ; Shao et al, 2022 ; Zhou et al, 2022 ).…”

Downregulation of RCN1 promotes pyroptosis in acute myeloid leukemia cells

“…Acute myeloid leukemia (AML) is a disease that exhibits high heterogeneity and a poor prognosis, with a high rate of recurrence [75]. Recent studies have found that a pyroptosis-related signature can effectively predict the prognosis of patients with AML [76,77]. The process of inflammation-related pyroptosis has emerged as a prospective target for cancer therapy [78].…”