AUTHOR=Hu Tingting , Zhang Yingjie , Yang Tianqing , He Qingnan , Zhao Mingyi 

TITLE=LYPD3, a New Biomarker and Therapeutic Target for Acute Myelogenous Leukemia

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.795820

DOI=10.3389/fgene.2022.795820

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> Acute myelogenous leukemia (AML) is nosocomial with the highest pediatric mortality rates and a relatively poor prognosis. <italic>C4.4A</italic>(<italic>LYPD3</italic>) is a tumorigenic and high-glycosylated cell surface protein that has been proven to be linked with the carcinogenic effects in solid tumors, but no hematologic tumors have been reported. We focus on exploring the molecular mechanism of <italic>LYPD3</italic> in the regulation of the occurrence and development of AML to provide a research basis for the screening of markers related to the treatment and prognosis.</p><p><bold>Methods:</bold> Datasets on RNA Sequencing (RNA-seq) and mRNA expression profiles of 510 samples were obtained from The Cancer Genome Atlas Program/The Genotype-Tissue Expression (Tcga-gtex) on 10 March 2021, which included the information on 173 AML tumorous tissue samples and 337 normal blood samples. The differential expression, identification of prognostic genes based on the COX regression model, and LASSO regression were analyzed. In order to better verify, experiments including gene knockdown mediated by small interfering RNA (siRNA), cell proliferation assays, and Western blot were prefomed. We studied the possible associated pathways through which <italic>LYPD3</italic> may have an impact on the pathogenesis and prognosis of AML by gene set enrichment analysis (GSEA).</p><p><bold>Results:</bold> A total of 11,490 differential expression genes (DEGs) were identified. Among them, 4,164 genes were upregulated, and 7,756 genes were downregulated. The univariate Cox regression analysis and LASSO regression analysis found that 28 genes including <italic>LYPD3</italic>, <italic>DNAJC8</italic>, and other genes were associated with overall survival (OS). After multivariate Cox analysis, a total of 10 genes were considered significantly correlated with OS in AML including <italic>LYPD3</italic>, which had a poor impact on AML (<italic>p</italic> &lt;0.05). The experiment results also supported the above conclusion. We identified 25 pathways, including the E2F signaling pathway, <italic>p53</italic> signaling pathway, and <italic>PI3K_AKT</italic> signaling pathway, that were significantly upregulated in AML samples with high <italic>LYPD3</italic> expression (<italic>p</italic> &lt; 0.05) by GSEA. Further, the results of the experiment suggested that <italic>LYPD3</italic> participates in the development of AML through the <italic>p53</italic> signaling pathway or/and <italic>PI3K/AKT</italic> signaling pathway.</p><p><bold>Conclusion:</bold> This study first proved that the expression of <italic>LYPD3</italic> was elevated in AML, which was correlated with poor clinical characteristics and prognosis. In addition, <italic>LYPD3</italic> participates in the development of AML through <italic>p53 or/and</italic> the <italic>PI3K/AKT</italic> signaling pathway.</p>