AML patients have benefited from advances in targeted molecular and immunotherapy [9, 10], but the 5-year survival rate of AML patients remains unsatisfactory due to high relapse rates. Stratification of patients into high- and low-risk groups based on reliable molecular signatures may aid in selecting appropriate treatment strategies in line with precision medicine. Many studies have reported a vital role of FRGs in tumorigenesis [11–13]. However, the relationship between AML prognosis and FRGs remains unclear. In this study, we established a novel ferroptosis-related prognostic gene signature for AML patients, and this is a first report. We assessed the relationship of 60 FRGs in AML tumor samples with OS and identified 18 FRDEGs which were differentially expressed in AML tissue compared with normal controls. Using LASSO Cox regression, we selected ten of these 18 FRDEGs for construction of a prognostic gene signature. We also compared enrichment score of infiltration of immune cells and immune pathways between high- and low-risk patients, investigated functional mechanisms using GSEA, and assessed potentially suitable drugs. This novel 10-gene signature may contribute to the improvement in the prediction of AML prognosis and patient stratification for therapeutic strategies.
The FRGs (CD44, CHAC1, CISD1, DPP4, NCOA4, SAT1, SLC7A11, AIFM2, G6PD, and ACSF2) are included in our 10-gene signature. CD44 is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion, and migration . Previously, it has been demonstrated that CD44 expression is closely related with the occurrence of tumors, including AML [15–17]. Stevens et al. found that CHAC1 contributes to the inhibition of AML via atovaquone . Genetic inhibition of CISD1 results in iron accumulation and subsequent oxidative injury in mitochondria, thus contributing to erastin-induced ferroptosis in HCC cells . Loss of TP53 prevents nuclear accumulation of DPP4 and thus facilitates plasma-membrane-associated DPP4-dependent lipid peroxidation, resulting in ferroptosis . CARS1 has been included in a novel prognostic signature by Chen et al., which effectively predicts the prognosis of Clear Cell Renal Cell Carcinoma . Activation of SAT1 induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon reactive oxygen species (ROS)-induced stress . Genetic inactivation of SLC7A11 has a synergistic effect with APR-246 for the promotion of cell death. G6PD has previously been proposed as a biomarker for AML . EBF3 acts as a tumor suppressor gene in AML, and AIFM2 is related to it . ACSF2 participates in the regulation of the lipid metabolism via peroxisome proliferator-activated receptor alpha. Recently, Wang et al. constructed a FRG signature for breast cancer patients, which included ACSF2 . Half of the genes included in our signature (CD44, CHAC1, SLC7A11, AIFM2, G6PD) were previously investigated in AML, whereas the other five FRGs have not previously studied in this context.
Recently, immune infiltration has been reported to be involved in the progression of AML. For example, Luca et al. found that the bone marrow immune environment of AML patients is profoundly altered . Jian et al. also found a higher level of B cell activation in AML samples than non-tumor samples . NK cell can trigger the anti-leukemia responses  and ferroptosis has been shown to exert anti-tumor immune effects by triggering dendritic cell maturation . Therefore, we explored the association between immune cell infiltration and the risk score in this study. Our data revealed that the high-risk group had a larger fractions of DCs, T cells, and NK cells. In addition, the high-risk group showed enrichment in many pathways including immune-related biological processes, such as antigen processing and presentation, B and T cell receptor signaling pathway, and NK cell mediated phagocytosis. Besides, in our tumor microenvironment correlation analysis, the risk score was positively associated with the immune score. Our findings revealed an association between the 10-gene signature and immune cell infiltration.
In the past few decades, targeted cancer therapies have advanced rapidly. However, treatment of AML remains unsatisfactory . In this study, we performed a drug sensitivity analysis to find AML drugs that may have clinical benefits. We found that G6PD and SAT1 were sensitive to 4 drugs (Mitomycin, ARRY-162, Cobimetinib, Irofulven), while CD44, SAT1, AIFM2, SLC7A11, and CHAC1 showed resistance to 12 drugs. These outcomes may provide further insights into treatment options for subgroups of AML patients. CSCs have been found play a crucial role in the occurrence and metastasis in AML. In this study, Cancer Stem Cell correlation analysis was significantly associated the risk score, however, more studies are required to prove the value of our 10-gene signature with CSCs in AML.
Our study has many advantages. Firstly, we first report a novel prognostic risk signature for AML based on ten FRGs. Secondly, we validated this 10-gene signature with clinical data. Thirdly, this signature revealed an association between FRGs and immune cell infiltration in AML. Finally, we found 4 drugs with potential have clinical advantages for AML treatment in the future. However, there are many limitations in our research. A single hallmark (ferroptosis) was used to construct a prognostic model, which may lead to the loss of many key prognostic genes of AML. In addition, the detailed roles of FRGs in AML should be further explored in the future.