Abstract 2997: Identification of novel long non-coding RNAs in mantle cell lymphoma patients

Abstract

Abstract Mantle Cell Lymphoma (MCL) is a rare and incurable type of B-cell non-Hodgkin lymphoma that affects about 4,000 people per year in the United States. Despite intense research to identify novel therapeutic approaches, the median progression-free survival after first-line treatment is four years. For this reason, the discovery of novel therapeutic targets remains crucial. Over half of the human genome is actively transcribed as non-coding RNAs. Among them, the non-coding RNAs that are longer than 200 nucleotides are named long non-coding RNAs (lncRNAs). lncRNAs have been shown to play essential roles in several human diseases, including cancer, by modulating cell cycle, immune response, or stemness through their interactions with DNA, protein, and RNA. For this reason, we decided to perform an RNA sequencing (RNA-Seq) profiling to identify the dysregulated lncRNAs in MCL. In more detail, we performed RNA-Seq in a cohort of 18 MCL patients compared to normal B-cells from the peripheral blood of healthy donors (HD). Reads were first trimmed for quality filtering, and adapters were removed using Trim Galore. Trimmed reads were mapped to the human genome (HG38 assembly) using HISAT 2. All the reads mapped inside the genomic coordinates of lncRNAs, reported in the GTF annotation file of GENCODE v43, were counted by featureCounts. Differential expression analysis between MCL samples vs HD was performed by LIMMA. To validate the results obtained from our internal MCL cohort, we also downloaded publicly available RNA-Seq data of 16 MCL patients and analyzed them using the previously described pipeline. Our analyses revealed several dysregulations in lncRNA expression occurring in MCL. Precisely, we identified 385 upregulated and 387 downregulated lncRNAs (|log2FC| > 0.58 and adjusted p-value < 0.05) in our internal MCL cohort, and 63% of them were also confirmed in the external cohort. Notably, the lncRNA called MALAT1 showed the highest significant upregulation in both cohorts, reinforcing this lncRNA's pivotal role in cancer development. To study the potential involvement of MALAT1 in MCL, we compared the MCL samples with higher MALAT1 expression (upper quartile) against those with lower expression (lower quartile) in both cohorts. The identified differentially expressed genes were used as input for a mechanistic network-based topological pathway analysis using MITHrIL. The analysis revealed that the KEGG pathway "Cell Cycle" was among the top upregulated pathways in MCL samples with high MALAT1 expression, suggesting the relevance of this lncRNA in promoting cellular proliferation, as also reported in the literature for other tumor types. In conclusion, our is the first study to describe the novel dysregulation signature of lncRNAs in MCL in two independent cohorts. Citation Format: Alessandro LaFerlita, Satishkumar Singh, Anuvrat Sircar, Robert Baiocchi, Natarajan Muthusamy, Lapo Alinari, Narendranath Epperla, Lalit Sehgal. Identification of novel long non-coding RNAs in mantle cell lymphoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2997.