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Dysregulation of ID gene expression has been revealed in various human cancers including AML, and was also associated with clinical outcome. Recently, Lu et al. using bioinformatics methods revealed that increased expression of ID1 and ID2 was correlated with poorer and better survival times, respectively, whereas ID3 and ID4 expression was not correlated with survival in lung adenocarcinoma patients []. Similarly, abnormal expression of ID genes may affect the occurrence and prognosis of lung cancer, and may be associated with cell metabolism and transcriptional regulation by using bioinformatics analysis []. These same results were further identified in breast cancer []. In the current study, by the bioinformatics analysis, we found that the expression of ID1 and ID3 was downregulated in AML, whereas the expression of ID2 was upregulated. Moreover, only abnormal ID3 expression may serve as an independent prognostic biomarker in AML and ID1/ID2 expression may independently affect clinical outcome in total AML. Previously, a few studies have reported the prognostic significance of ID gene expression in AML. Tang et al. revealed that high ID1 expression was correlated with adverse prognosis in AML []. However, a later study demonstrated that overexpression of ID1 was not an independent prognostic biomarker in young CN-AML patients []. Interestingly, our previous study indicated that overexpression of ID1 was correlated with higher karyotypic risk classification and served as an independent risk factor in young (age < 60 years) non-M3 patients []. Meanwhile, overexpression of ID2 was a frequent event in patients with AML and predicted poor chemotherapy response and clinical outcome []. Conversely, promoter hypermethylation-mediated ID4 repression was linked to disease progression in MDS and poor prognosis in AML. Altogether, these different results may be attributed to the differences in ethnicity and in AML subtype distribution. Accordingly, further studies are needed to validate the expression and clinical implications of the ID genes in AML.

In the present study, we mainly focused on ID3 expression in AML based on the bioinformatics identification and experimental validation. For the first time, we revealed that ID3 expression could serve as a prognostic predictor in AML. Notably, it is very interesting that ID3 could independently affect OS but not DFS by multivariate Cox regression analysis. We deduced that the role of aberrant ID3 expression in AML survival was not directly mediated by influencing leukemia development but could affect multiple factors that lead to all-cause death in AML. Previously, only May et al. revealed that ID2 and ID3 protein expression mirrored granulopoietic maturation and discriminated between acute leukemia subtypes []. However, numerous studies have investigated the expression and prognostic value of ID3 in human solid tumors. Xu et al. demonstrated that ID3 played a tumor suppressive role in papillary thyroid cancer and impeded metastasis by inhibiting E47-mediated epithelial to mesenchymal transition (EMT) []. Huang et al. indicated that ID3 could enhance the stemness of intrahepatic cholangiocarcinoma by gaining the transcriptional activity of β-catenin and could act as a potential biomarker in predicting response to adjuvant chemotherapeutics []. Moreover, ID3 overexpression was correlated with medulloblastoma seeding and is a poor prognostic factor in medulloblastoma patients []. Sharma et al. revealed that ID1 and ID3 overexpression alleviated all three cyclin-dependent kinase inhibitors (CDKN2B, -1 A, and − 1B) resulting in a more aggressive prostate cancer phenotype []. Expression of ID1 and ID3 was increased in human invasive lobular carcinoma compared with invasive ductal carcinoma, associated with poor prognosis uniquely in patients with invasive lobular carcinoma and correlated with the upregulation of angiogenesis and matrisome-related genes []. In addition to the above results, several studies have also reported the value of the combination of ID3 expression with other members in cancer prognosis. For instance, Antonângelo et al. showed that ID1, ID2 and ID3 coexpression was associated with prognosis in stage I/II lung adenocarcinoma patients treated with surgery and adjuvant chemotherapy []. Additionally, ID1 and ID3 coexpression was correlated with a poor clinical outcome in patients with locally advanced non-small cell lung cancer treated with definitive chemoradiotherapy []. The combined expression of VPREB3 and ID3 was used to develop a new helpful tool for the routine diagnosis of mature aggressive B-cell lymphomas []. All these results suggested the prognostic value of ID3 expression in diverse human cancers.

The functional role of ID3 has also been widely investigated, and was reported to be associated with diverse biological processes such as angiogenesis, apoptosis, cell cycle regulation/proliferation, cell migration/invasion, epithelial-to-mesenchymal transition, stem cell renewal and signaling []. Although we did not validate the direct role of ID3 in AML in this study, we identified the association of ID3 with PI3K/AKT signaling by bioinformatics methods. Moreover, the association of low ID3 expression with FLT3 mutation was also observed in AML patients. Similarly, Chen et al. demonstrated that miR-212-5p was involved in the progression of non-small cell lung cancer through the activation of PI3K/Akt signaling pathway by targeting ID3 []. Zhang et al. indicated that Per2 downregulated ID3 expression via the PTEN/AKT/Smad5 axis to inhibit glioma cell proliferation []. Moreover, ID3 was reported to play a significant role in reversing cisplatin resistance in human lung adenocarcinoma cells by regulating the PI3K/Akt pathway []. Accordingly, further functional studies are needed to confirm the direct role of ID3 in AML biology.

The regulatory mechanism of ID3 expression was preliminarily studied. Xu et al. demonstrated that hypermethylation of the CpG island at the promoter region of ID3 was the main contributor to the repression of this gene []. In addition, several studies also revealed the regulatory potential of miRNAs. Zhao et al. found that miR-326 could bind to ID3, which accelerated the development of medulloblastoma []. Moreover, high ID3 expression by silencing miR-212-5p expression suppressed the activity of the PI3K/Akt signaling pathway and consequently promoted apoptosis and inhibited proliferation in lung cancer cells []. Herein, we also observed the association of ID3 with several miRNAs such as miR-1259, miR-508, miR-9, miR-944, let-7b, miR-141, and miR-223. However, only miR-326 was confirmed by previous studies []. Accordingly, further studies are needed to confirm the direct association of ID3 with these miRNAs.