The family of STAT genes is thought to originate from successive genome duplication and functional divergence of a single ancestral STAT gene early in vertebrate evolution. Typically, each of the STAT family members is a target gene induced when the respective transcription factor is activated. Many upstream kinases can activate STATs, though the most common is the Janus kinase, which associate with various cell surface receptors. Janus kinases are a family of non-receptor tyrosine kinases that primarily transduce signals from the cell surface to the nucleus by activating downstream STATs. Subsequently, STATs translocate to the nucleus and bind with DNA to transcribe genes that are involved in cellular proliferation, survival, angiogenesis and immunity. In cancer, STATs can become activated constitutively due to aberrant activation of an upstream kinase and/or loss of a negative regulator, leading to the changes in gene expression that underlies the malignant phenotype. Although the role of STATs in the occurrence and prognosis of certain cancers has been clarified, there are very few reports on the expression and role of different STATs in AML. In this study, we explored the transcription level, molecular mechanism, and biological function of STATs in AML and its relationship with prognosis and immune infiltration in patients with AML.
Based on the available evidence, the role of STAT1 in patients with cancer remains controversial. Moreover, the mechanism behind the oncogenic or tumor-suppressing role of STAT1 remains unclear. STAT1 deficiency studies show that STAT1 act as a tumor promoter in leukemia development25. Of the STAT family, only STAT1 and STAT2 are critical for the IFN pathway26. However, little is known about the function of STAT2 in malignancy. Similar to STAT2, previous studies on STAT4 in malignancy are limited. Moreover, functions of STAT4 in carcinogenesis and tumor metastasis are paradoxical. STAT6 is a key member of the STAT family, whose role in the biology of lymphoma and leukemia has been firmly established27. Our research shows that STAT1, STAT2, STAT4 and STAT6 are highly expressed in AML, but only STAT6 has an effect on survival. Nevertheless, the expression levels of STAT3, STAT5A, and STAT5B were lower in AML than in normal tissues. Although STAT3 activation is transient and dispensable in normal cells, it often occurs constitutively in cells of many hematological (and solid) cancers, which depend on STAT3 for survival28. STAT3 is constitutively activated in various human cancers, and its activation is frequently associated with poor prognosis. STAT5 has two highly homologous isoforms, STAT5A and STAT5B. Although STAT5 has been implicated in several cancers for tumor proliferation, apoptosis and invasion, the majority of studies reported STAT5 genes predicted a favorable clinical outcome in malignancy. In this study, we found that STAT3 levels have no bearing on the prognosis of AML patients. In addition, our current results indicate that the high expression of STAT5B is related to the improvement of OS in AML patients, but there is no correlation between the expression of STAT5A and OS in AML patients. Liu et al. reported that expression levels of STAT2, STAT4 and STAT6 were significantly higher in AML than in normal tissues. Furthermore, high expression of STAT6 was correlated to lower OS in AML patients29. Intriguingly, our study shows that more members of STATs are differentially expressed between AML and normal tissues. In addition, we found that high expression of STAT6 is associated with lower OS, and high expression of STAT5B is associated with better OS. This can be attributed to different study design, sample size and cutoff. However, by multivariate analyses and constructing the LASSO model, we proved that STAT5B expression is an independent marker for the prognosis of AML. To the best of our knowledge, this is the first report investigating the relationship between STAT5B and prognosis of AML.
We assessed the function of STATs by GO enrichment analysis and KEGG pathway enrichment in human. Then we used DisGeNet and found that STATs are highly correlated with myeloid leukemia. DisGeNET is a newly developed platform that covers a comprehensive catalog of genes and variants related to human diseases30. It collected 4145 genes related to 738 tumor diseases, deepening our understanding of the link between genetic variation and cancer incidence and progression. Through the single-gene difference combined enrichment analysis, we predicted functions and pathways that STAT5B may participate in. Studies have revealed that the function of STAT5B is significantly related to the occurrence, development and tumor microenvironment of AML.
In solid tumors, the tumor genetic environment directly regulates the anti-tumor immune response and the efficacy of immunotherapy31. The genetic changes of AML cells have been extensively studied and deeply understood, but there are few studies on the immunological characteristics of AML. The result of this study is that the expression level of STAT5B was positively correlated with infiltration of T cells, while it was negatively correlated with infiltration of dendritic cells. The key step in activating the immune system is to recognize the surface antigens of tumor cells. Because T cells naturally traffic to hematopoietic sites where AML localizes, T-cell therapy has significant potential. AML cells are essentially the precursors of dendritic cells antigen presenting cells, but their ability to produce effective immune responses is weak. This may be explained by the inability to form effective immune synapses and present antigens to T cells32. Comprehensive immune profiling of newly diagnosed AML patients proved that the functional defects of T cells and NK cells are the main aspects of immune dysfunction, while the function of B cells is not affected33. The senescence and exhaustion of T cells, the over-maturation of NK cells and impaired function of γδT cells all participate in immunosuppression, causing AML cells to evade immune attack.