AUTHOR=Chen Long , Xiong Zujian , Zhao Hongyu , Teng Chubei , Liu Hongwei , Huang Qi , Wanggou Siyi , Li Xuejun 

TITLE=Identification of the novel prognostic biomarker, MLLT11, reveals its relationship with immune checkpoint markers in glioma

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.889351

DOI=10.3389/fonc.2022.889351

ISSN=2234-943X

ABSTRACT=<sec><title>Aim</title><p>This study aimed to explore the expression pattern of <italic>MLLT11</italic> under different pathological features, evaluate its prognostic value for glioma patients, reveal the relationship between <italic>MLLT11</italic> mRNA expression and immune cell infiltration in the tumor microenvironment (TME), and provide more evidence for the molecular diagnosis of glioma and immunotherapy.</p></sec><sec><title>Methods</title><p>Using large-scale bioinformatic approach and RNA sequencing (RNA-seq) data from public databases The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and The Gene Expression Omnibus (GEO)), we investigated the relationship between <italic>MLLT11</italic> mRNA levels and pathologic characteristics. The distribution in the different subtypes was observed based on Verhaak bulk and Neftel single-cell classification. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used for bioinformatic analysis. Kaplan–Meier survival analysis and Cox regression analysis were used for survival analysis. Correlation analyses were performed between <italic>MLLT11</italic> expression and 22 immune cells and immune checkpoints in the TME.</p></sec><sec><title>Results</title><p>We found that <italic>MLLT11</italic> expression is decreased in high-grade glioma tissues; we further verified this result by RT­PCR, Western blotting, and immunohistochemistry using our clinical samples. According to the Verhaak classification, high <italic>MLLT11</italic> expression is mostly clustered in pro-neutral (PN) and neutral (NE) subtypes, while in the Neftel classification, <italic>MLLT11</italic> mainly clustered in neural progenitor-like (NPC-like) neoplastic cells. Survival analysis revealed that low levels of <italic>MLLT11</italic> expression are associated with a poorer prognosis; <italic>MLLT11</italic> was identified as an independent prognostic factor in multivariate Cox regression analyses. Functional enrichment analyses of <italic>MLLT11</italic> with correlated expression indicated that low <italic>MLLT11</italic> expression is associated with the biological process related to the extracellular matrix, and the high expression group is related to the synaptic structure. Correlation analyses suggest that declined <italic>MLLT11</italic> expression is associated with increased macrophage infiltration in glioma, especially M2 macrophage, and verified by RT­PCR, Western blotting, and immunohistochemistry using our clinical glioma samples. <italic>MLLT11</italic> had a highly negative correlation with immune checkpoint inhibitor (ICI) genes including <italic>PDCD1</italic>, <italic>PD-L1</italic>, <italic>TIM3(HAVCR2)</italic>, and <italic>PD‐L2 (PDCD1LG2)</italic>.</p></sec><sec><title>Conclusion</title><p><italic>MLLT11</italic> plays a crucial role in the progression of glioma and has the potential to be a new prognostic marker for glioma.</p></sec>