Acute myeloid leukemia (AML) is a clonal malignant proliferative disease of myeloid primitive cells in the hematopoietic system, and it is highly heterogeneous. AML can be transformed into malignant changes of hematopoietic progenitors at different stages of normal myeloid cells (1). Currently, the treatment of AML mainly includes chemotherapy, biologics, and hematopoietic stem cell transplantation (HSCT) (2), but about 70% of patients who achieve remission will eventually relapse or evolve into refractory leukemia, leading to treatment failure and death (3). The prognosis and survival rate of AML prognosis are unsatisfactory, and it has been reported the 5-year overall survival (OS) ratein young AML patients is less than 50%, and the 2-year OS rate in older patients after diagnosis is only 20% (4).

Pyroptosis, also known as cell inflammatory necrosis, is a programmed cell death (5), It is mainly manifested as the cell membrane rupture, leading to the release of cell contents and then activation of strong inflammatory response (6). Pyroptosis plays an important role in the fight against infection, and it is widely involved in the development of infectious diseases and nervous system-related diseases (7). Moreover, Johnson et al. found that small-molecule inhibitors of the serine dipeptidases DPP8 and DPP9 (DPP8/9) induced-pyroptosis in mouse and human monocytes and macrophages for treatment of AML, it also shown that there is a strong correlation between pyroptosis and antileukemic therapy (8).

RNA-binding proteins (RBPs) are a general term for a group of proteins that perform their functions by specifically binding to RNA. To date, the human genome-wide screen has identified 1,542 RBP genes, accounting for 7.5% of all egg and white matter-encoding genes (9). RBP plays a crucial role in processes such as RNA maturation, transport, localization and translation, and it is also vital in gene expression and maintenance of genomic integrity (10, 11). Currently, Kharas et al. found that RBPs of the musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia, it may be as a new prognostic marker and target for therapy in AML. However, there are still few reports on the relationship between pyroptosis and RBPs (12).

Cell pyroptosis is closely related to RBPs. Mast cells can identify the nucleic acid fragments (DNA or RNA), bacterial cell wall components (LPS), and flagella of these pathogenic microorganisms, thus stimulating immune measures, which can lead to the pathogen elimination by immune cells (13). However, there was no report on the RBPs associated with cell pyroptosis in patients with AML in public database. In this study, the RBP genes related to cell pyroptosis in AML patients were studied by bioinformatics analysis methods, and they were constructed and verified by the prognostic feature model, providing new ideas for clinical treatment.

Acute myeloid leukemia is one of the most common malignant hematological and systemic diseases in adults, which is mainly characterized by susceptibility to relapse, poor prognosis, and low survival rate (1, 3, 4). Pyroptosis is a programmed death (5), and RBPs are essential modulators of transcription. Kebin Huang et al. found that MicroRNA-519 enhances HL60 human acute myeloid leukemia cell line proliferation and induces cell apoptosis by reducing the expression level of RBPhuman antigen (18). Additionally, B Mitton et al. reported that a small molecule inhibitor of CREB (cAMP Response-Element Binding Protein), XX-650-23, interaction mostly affects apoptotic, cell-cycle, and survival pathways, which may represent a novel approach for AML therapy (19). However, the relationship between pyroptosis-related RBPgenes and AML remains unclear, so it is important to predict the relationship between pyroptosis-related RBPgenes and AML.

In this study, 71 PRBP DEGs were enriched to cellular protein complex disassembly, RNA catabolic process, RNA transport, RNA destabilization, negative regulation of protein acetylation, ribonucleoprotein complex assembly, and protein export from protein-related pathways such as nucleus. In a study on the expression pattern and clinical value of key m6A RNA modification regulators in abdominal aortic aneurysm, it found that the modified genes were primarily enriched in RNA catabolic process, RNA transport et al. (20). Nelsonet al. demonstrated that a block to efficient splicing can occur at multiple steps in the pathway of normal splicing complex assembly, and plice site selection and ribonucleoprotein complex assembly during in vitro pre-mRNA splicing (21). However, the role of the above enriched pathways in AML has not been reported. Stefan Gattenloehner et al. found that the CD56 expression on AML cells correlates with an abnormal expression pattern of runt-related transcription factor 1 (RUNX1) isoforms and the potential for new therapy of CD56(high) AML by suppression of the “overactive” RUNX1/CD56/NF-kappa B signaling pathway(s) (22). Therefore, we guess that certain pathways play an important role in the pathogenesis of AML, and in the future work, we need to further focus our attention on the significance of the enriched pathways such as cellualr protein complex disassembly in AML.

We constructed a risk model of the RBP genes associated with cell pyroptosis in patients with Acute Myeloid Leukaemia. Yi Zhang et al. constructed a novel prognostic scoring model for newly diagnosed FLT3-ITD-positive AML (23), but the model has some limitations such as induction and consolidation treatment regimens cannot be fully harmonized due to the retrospective nature of the study. Yun Wang et al. built an immune risk score to predict survival of patients with AML receiving chemotherapy (24), however, they lacked data on some important predictive covariates, such as mutation topography and results of MRD testing in subjects achieving a complete remission. Piyanuch Kongtim et al. constructed anovel disease risk model for patients with AML receiving allogeneic hematopoietic cell transplantation (25), while this is a retrospective study conducted in a single institution, and the limited number of patients in some subgroups may not detect relevant differences between the groups. Compared with the above models, the risk model we constructed started from the direction of the RBP genes associated with cell pyroptosis. Meanwhile, it had the advantage of fewer model genes.

In constructing this prognostic-related risk model, we obtained a total of six biomarkers. IFIT5, MRPL14, MRPL21, MRPL39, and PUSL1, and none of these genes have yet been reported in AML. MVP encodes the major component of the vault complex. The encoded protein may play a role in multiple cellular processes by regulating the MAP kinase, JAK/STAT and phosphoinositide 3-kinase/Akt signaling pathways. The encoded protein also plays a role in multidrug resistance, and expression of this gene is a prognostic marker for several types of cancer. However, H J Broxterman et al. found that it is shown that Pgp function, but not Mvp/LRP or MRP1 expression correlate with a low steady-state DNR accumulation in de novo AML. The Pgp activity does, however, not predict the DNR sensitivity in AML measured as in vitro DNR LC50 with an MTT-based assay. The reason for that seems to be that a low DNR accumulation may not be the most important factor in determining the LC50 (26). Therefore, the drug resistance effect of MVP in AML still needs further investigation.

In this study, we performed pathway enrichment analysis between high and low risk groups using GSEA software, and finally analyzed differentially expressed genes between high and low risk groups using the R package limma, and performed functional enrichment analysis of differential genes using the enrichment tool DAVID. Our findings found that the high- and low-risk groups were associated with several immune-related and metabolic-related biological processes and pathways. The high-risk group was associated with activation of the innate immune response and innate immune response activating signal transduction. Curran et al.’ laboratory has recently characterized the host innate immune system generates a T cell tolerant state in an animal AML model (27). Antigen-specific T cell tolerance is a potent immune evasion mechanism in hosts with AML that can be reversed in vivo after CD40 engagement (28). These results indicate that immune tolerance to AML may be initiated at the level of the innate immune system (27, 28). Long Zhang et al. discovers antigen-specific T cell tolerance is a potent immune evasion mechanism that can be reversed in vivo after CD40 engagement via a murine AML model (28). Our findings are consistent with those of the above investigators. Marko Skrtic et al. found that inhibition of mitochondrial translation as a therapeutic strategy for human AML (29). Marvin M van Luijn et al. found that the myeloid leukemic blasts with expressing HLA class II molecules, abnormalities in the processing pathways of endogenous antigens could also result in impaired HLA class II-restricted tumor-associated antigen presentation to CD4(+) T helper cells (30). Hideaki Mizuno et al. revealed that suppression of Fbp1, as well as pentose phosphate pathway enzymes by shRNA-mediated knockdown selectively decreased Evi1-driven leukemogenesis in vitro, Considering Evi1 upregulates Fbp1, and supports progression of AML through pentose phosphate pathway activation. Our findings also found that the high-risk group was associated with mitochondrial transport, antigen processing and presentatio and pentose phosphate pathway. Overall, the functional enrichment results for high- and low-risk groups suggested the linkages between RBPs associated with cell pyroptosis and metabolism in AML.

Some limitations of this study also exist, (a) Some functional experiments were needed to further illustrate the underlying molecular mechanisms to predict the role of the cellular pyroptosis-related differential RBP genes in AML; (b) The prognostic model should be validated by more datasets and clinical samples; (c) This study only used bioinformatics methods to conduct multiple analyses based on retrospective data from the public databases, confirmatory experiments in vivo and in vitro will be required subsequently. Therefore, we will continuously focus on the role of these genes.

In conclusion, through the above analysis, the differential RBP genes related to pyroptosis in AML were screened, and through the regression analysis of these genes, six biomarkers were obtained, and a risk model associated with metabolism was constructed, which provided a theoretical basis and reference value for the future treatment research and prognosis of AML.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .

TB and CL are the principal investigator and conducted statistical analysis and drafted the article. JT and BL performed data management and bioinformatics analysis. TB, CL, F-JL, YW, X-JX, D-JL, JT, and BL edited and revised the article. All authors have read and agreed to the published version of the manuscript.

This research was supported by Sanming Project of Medicine in Shenzhen (No.SZSM201911004).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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