Abstract

Background: Interleukin 16 (IL16) is a pleiotropic cytokine that does not belong to any interleukin family and functions as a CD4⁺ T-cell chemokine, a regulator of T-cell activation, and an inhibitor of human immunodeficiency virus replication in acquired immunodeficiency syndrome. Studies in the hemato-oncological disease multiple myeloma have demonstrated that IL16 plays an important role in promoting tumor cell growth and is associated with tumor burden and prognosis. However, the role of IL16 in acute myeloid leukemia (AML) remains largely unexplored.

Aims: To investigate the potential role of IL16 in AML.

Study Design: In vitro experiments.

Methods: Bioinformatic analyses were conducted using online databases, including gene expression profiling interactive analysis 2, to evaluate IL16 expression and its prognostic significance in patients with AML. Transcriptome data from AML samples were used for gene function enrichment analysis, gene set enrichment analysis (GSEA), survival analysis, and other related bioinformatic assessments. In addition, a single-cell dataset was analyzed using the R programming language to identify specific IL16 expression subgroups in AML patients. The expression and secretion of IL16 in various AML cell lines were assessed using Western blot and ELISA. IL16 knockdown AML cell lines were generated and evaluated for proliferation, apoptosis, and multidrug resistance to chemotherapy using cell-based assays and protein immunoblotting to determine the effects of IL16 on AML biological behavior. Furthermore, transcriptome sequencing analysis was performed to elucidate the molecular mechanisms underlying the effects of IL16 on the biological functions of AML cells.

Results: IL16 expression levels were significantly elevated in patients with AML and were associated with poorer prognosis. IL16 was predominantly expressed in T cells, malignant hematopoietic stem cells, malignant progenitor cells, and malignant mononuclear precursor cells in AML patients. Knockdown of IL16 expression significantly inhibited proliferation and promoted chemotherapy-induced apoptosis in AML cells in vitro. Downregulation of IL16 also reduced cell viability and decreased the IC50 of cytarabine (Ara-C) across different concentrations. Furthermore, reduced IL16 expression may induce degradation of mutated TP53 in AML cells, resulting in increased apoptosis and enhanced sensitivity to multiple chemotherapeutic agents.

Conclusion: High IL16 expression was observed in malignant cells from patients with AML. Downregulation of IL16 promotes degradation of mutant TP53 and induces apoptosis, thereby increasing the sensitivity of AML cells to various chemotherapeutic agents in vitro.