In this study, we screened out AML relapse-related DEGs based on TCGA and GSE134589 datasets. The up-regulated DEGs were strikingly enriched in the immune signaling pathway, Cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway,and Th17 cell differentiation, and the down-regulated DEGs in Cytokine-cytokine receptor interaction, Tumor necrosis factor (TNF)-signaling pathway and RIG-I-like receptor signaling pathway. We further screened out 332 hub DEGs, most of which were enriched in the positive regulation of mononuclear cell proliferation, leukocyte migration, cytokine biosynthetic proces, lymphocyte proliferation, phospholipase activity, and T cell costimulation enents.
Cytokine-cytokine receptor interaction plays a significant role in the pathogenesis of various types of lymphomas (26). Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) are protective immune guards, which can initiate signaling pathways completing activation of NF-kappaB, MAP kinases, and IRFs that manage the transcription of genes encoding type I interferon and other inflammatory cytokines (27, 28). Previous studies have delineated that TLRs are in connection with hematopoietic damage, leading to expanded HSC proliferation and an increased bias toward myeloid cell differentiation, contributing its strength to the development of hematopoietic malignancies and bone marrow failure (29–32). This may be owing to the release of proinflammatory cytokines that could form a microenvironment accessory to promoting tumorigenesis. Th17 cells were known as a subgroup of Th cells showing proinflammatory as well as tumor-promoting qualities in diverse cancer types (33, 34). The TNF-signaling pathway is a principal mediator of apoptosis, inflammation, and immunity, and it has been implicated in the pathogenesis of a broad spectrum of human diseases, including diabetes, cancer, and different type of inflammatory diseases (35). Similarly, researches have illustrated that regulation of phospholipase activity fosters the development of tumors (36). It is not difficult to find that DEGs were mainly enriched in the immune regulation, as same as inflammation and apoptosis pathways, exhibiting proinflammatory and tumor-promoting characteristics, play an important role in generating a microenvironment conducive to the extension of tumor cells. All these findings point out the possible relationship between some DEGs and relapse AML development, which may give a new direction for relapse AML research.
Through the enrichment of DEGs, we found that most of the genes related to the recurrence of AML are gathered in the immunocorrelation pathways. Earlier studies have also told that the immune response plays an essential role in the evolution and migration of various tumors, and immunotherapy and targeted therapy are also considered as two dominant agents in tumor therapy in addition to chemotherapy. Therefore, in this study, CIBERSORTx algorithm was used to presume the percentage of 22 TIICs subsets from AML transcriptomes from OHSU and GSE134589 databases, and to reveal distinguished patterns of TIICs in initial and recurrent AML, as well as the associations between different immune cell subsets with clinical outcomes. We observed notable differences in immune cell composition between relapse AML and denovo AML. Compared with denovo AML, relapsed AML contained a greater number of Neutrophils. However, Plasma cells,T cells CD4 naive, Macrophages M2༌T cells CD4 memory resting༌Dendritic cells resting༌Mast cells resting, and Eosinophils fractions were relatively lower. Moreover, our work validated the findings that certain immune cell subsets can also predict clinical outcomes besides the Immunocore. By univariate Cox regression analysis, we found that T cells CD4 memory activated and Macrophages M2 are significantly associated with poor outcome. Paradoxically, in this study, the immune cell subpopulation, which forecasted poor prognosis, did not have a significantly high expression in relapsed AML. On the contrary, Macrophages M2 expressed lower than that of denovo AML, while T cells CD4 memory activated made no significant difference. Since only two data sets were included in this study, and only 53 patients in one data set were used for immune-related prognostic analysis, more clinical data will be needed to investigate the role of immune cell subsets in relapsed AML. It's worth noting that in multiple situations the immune function may vary greatly, although there is no difference in the number of immune cells. Subsequent studies can specifically study the functions of T cells and macrophages in the recurrence of AML.
We found the expression of ALDH1L2, KLK1,and LRRN2 were significantly different in relapse and denovo AML, and were negatively related to the overall survival of the AML patients. ALDH1L2 encodes for a mitochondrial FDH and is involved in controlling the metabolic period of tetrahydrofolate (THF) in mitochondria. In recent years, the significance of mitochondrial metabolism in tumor cells has attracted more and more attention. ALDH1L2 has been shown to promote melanoma metastasis in vivo, and shorter survival has been reported in colorectal and lung adenocarcinoma studies(37–39). KLK1 belongs to the serine protease family of proteolytic enzymes, and growing evidence suggests that many KLKs are implicated in carcinogenesis(40). LRRN2༌also known as GAC1, was found overexpressed in malignant gliomas༌and is a candidate for the target gene in the 1q32.1 amplicon in malignant gliomas(41). In the present study, we verified the prognostic value of ALDH1L2, KLK1༌and LRRN2 in AML, which broadens the landscape of ALDH1L2, KLK1༌and LRRN2 research, and can guide the future exploration into relapse AML mechanism.