Multiple myeloma (MM) is the second most prevalent hematologic malignancy [2]. Since the pathogenesis of MM is still not fully elucidated due to its high genetic heterogeneity and the complex regulation of tumor cells and bone marrow microenvironment, it is still incurable. Therefore, searching for disease prognostic factors, potential pathogenic genes and drug resistance targets of MM and elucidating their mechanisms of action by using bioinformatic analysis is expected to provide effective therapeutic targets for clinical purposes.
The ALG3 gene, also named alpha- 1,3- mannosyltransferasegene, is located at 3q27.1. The protein encoded serves the catalytic function of mannosyltransferase. Few studies on the ALG3 gene have been conducted, mainly focusing on diabetes mellitus, congenital glycosylation disorders and other glucose metabolism-related diseases [20]. Studies have shown that ALG3 is involved in tumor development, namely, ALG3 is closely related to tumorigenesis through its involvement in the glycosylation process of tumor cells, and there is increasing evidence that abnormal glycosylation process can be used as a biological marker of tumor cells [21]. Moreover, high expression and poor prognostic significance of ALG3 in head and neck squamous carcinoma [22] and breast cancer [23] have been reported in the literature. Further, ALG3 can be used as a novel biomarker for 3q27 amplification in esophageal squamous carcinoma [24]. In the few studies related to ALG3 and hematologic malignancies, we found that aberrant mannosylation process and FTX/miR342/ALG3 axis promote drug resistance in acute myeloid leukemia (AML) [25]. The expression of ALG3 in MM has not yet been published in the literature, and in this paper, a novelty is pioneered to report
the expression of ALG3 in MM cells and its correlation with cytogenetic abnormalities, and to analyze the impact of its expression level on patient prognosis.
Based on the Oncomine database, this article deeply explored the information of MM-related datasets and found that the expression level of ALG3 in MM cells was significantly higher than that in normal subjects and was closely associated with the shortened survival time of patients. Meanwhile, CCLE database information showed that the average expression level of ALG3 in MM cell lines was higher than the average expression level in other tumor cell lines which suggests that our abnormally high expression of ALG3 in MM may play a role in the development of the disease.
Further analysis showed that ALG3 high expression was a poor prognostic factor in MM whose prognostic significance was not disturbed by 1q21 amplification. Subgroup analysis provides a fine- grained perspective for analyzing data to accommodate the heterogeneity inherent in clinical research. Examining the possible impact of different treatments on survival ensures that key findings are consistent across subgroups and not just artifacts of specific subgroups. Similarly, the Mulligan myeloma dataset stratified samples according to treatment with bortezomib (BTZ, PS-341)
or dexamethasone (due to the varying mechanisms of action and treatment responses to these drugs). Thus, subgroup delineation is essential to determine the prognostic significance of ALG3 in
treatment.
The chromosomal region 1q21 is a frequent site of genetic abnormalities in multiple myeloma (MM). Amplification or gain of 1q21, often referred to as " 1q21+", is associated with a poor prognosis in MM patients. This region contains several genes that are believed to play a role in the pathogenesis and progression of MM, making it a key area of interest for researchers. If ALG3 is found to be a poor prognostic molecule regardless of the 1q21 + status, it might serve as an independent prognostic marker, allowing for more nuanced risk stratification of MM patients. This could help in tailoring therapeutic approaches for different patient subgroups. Additionally, understanding the independent role of ALG3 can shed light on its specific biological functions and its potential as a therapeutic target.
GO and KEGG pathway enrichment analysis of ALG3 and its co-expressed molecules showed that ALG3 is involved in RNA degradation, proteasome regulation, HIF- 1 signaling pathway and shear body formation pathways. In particular, ALG3 is involved in proteasome regulation which suggests that ALG3 is probably involved in the resistance of MM tumor cells to proteasome inhibitors. However, since only the differential expression of ALG3 at the mRNA level and its potential
functions were analyzed, the differences in expression at the protein level and the specific signaling pathways involved remain to be experimentally verified.
Although current research has focused on the prognostic relevance of ALG3, its potential role in drug resistance is also an avenue worth exploring. Elevated gene expression in cancer often leads to give rise to drug resistance mechanisms [26]. For example, proteasome inhibitors such as bortezomibhave been shown to be resistant in the treatment of MM [27]. ALG3 may affect cellular responses to drugs such as bortezomib through as yet unidentified mechanisms, paving the way for resistance to develop.
In summary, this paper used bioinformatic analysis to investigate the information in Oncomine and CCLE databases, and found that ALG3 is abnormally highly expressed in MM and is an independent poor prognostic factor for MM, which is expected to provide precise therapeutic targets for the clinic.