CCR9 overexpression promotes T-ALL progression by enhancing cholesterol biosynthesis

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of the lymphoid progenitor cells contributing to [~] 20% of the total ALL cases with higher prevalence in adults than the children. Despite the important role of human T-ALL cell lines in understanding the biology and treatment options, a detailed comparison of the tumorigenic potential of two commonly used T-ALL cell lines, MOLT4 and JURKAT cells is still lacking. In the present study, we compared the leukemogenic potentials of the two T-ALL cell lines (MOLT4 and JURKAT) in NOD-PrkdcscidIL2rgdull (NTG) mice and found that MOLT4 cells possessed a relatively higher aggressive phenotype characterized by their enhanced tissue infiltration as compared to the JURKAT cells. Gene expression profiling of the two cell lines revealed numerous differentially expressed genes (DEGs) including CC chemokine receptor 9 (CCR9), which augmented the invasion and metastasis of MOLT4 and JURKAT cells in vitro. The upregulation of CCR9 also promoted the tissue infiltration of JURKAT cells in the NTG mice. CCR9 overexpression increased cholesterol production by upregulating the expression of the core regulatory genes of the cholesterol biosynthesis pathway including MSMO1, MVD, and HMGCS1. Moreover, the upregulated expression of EGR1 was also found with CCR9 overexpression that modulated the expression of MSMO1, MVD, and HMGCS1. Notably, the treatment of the cells with simvastatin and siRNA-EGR1 decreased the aggressiveness of the CCR9 overexpressing JURKAT cells in vitro, suggesting the CCR9-EGR1 axis in T-ALL progression. This study highlights the distinct tumorigenic potentials of two T-ALL cell lines and reveals CCR9-regulated enhanced cholesterol biosynthesis in T-ALL. Simple summaryT-ALL is an aggressive cancer of the blood and bone marrow. In order to understand the biological mechanism of T-ALL, in vitro T-ALL cell lines are commonly employed. However, a comprehensive comparison of two common T-ALL cell lines, MOLT4 and JURKAT cells for T-ALL development is not yet available. We compared MOLT4 and JURKAT cells for T-ALL inducing potential and found that MOLT4 cells exhibited a relatively increased aggressiveness in mice as compared to JURKAT cells. We examined the molecular characteristics of two cell lines that could lead to differences in cancer development. Transcriptional profiling of MOLT4 and JURKAT cells revealed significant changes in the expression of several genes including CCR9. This aberrant expression of CCR9 impacted the migration and invasion of the T-ALL cell lines in vitro. In addition, higher expression levels of CCR9 also promoted T-ALL progression in vivo. Transcriptome analysis and gene ontology analysis of the DEGs of CCR9 over-expressing JURKAT cells indicated the enrichment of the genes in the cholesterol biosynthesis pathway, suggesting this metabolic rewiring mechanism as a strategy to cope with the increased energy demand of the malignant T-ALL cells.