Somatic FOXC1 insertion mutation remodels the immune microenvironment and promotes the progression of childhood acute lymphoblastic leukemia

Background: Children acute lymphoblastic leukemia (ALL) is the most common malignant hematemesis in children. Immunosuppressive microenvironment especially regulatory T cells (Treg) infiltration has been documented highly associated with children ALL. This present project based on genetic factors, aiming to investigate the potential mutation involved in the immunosuppressive microenvironment of children ALL.Methods: The whole-exome sequencing was employed in DNA extracted from the T cells of ALL bone marrow samples. After analyzing, cells were treated with either wild type or mutant of FOXC1 in T cells cultured in vitro. T cell subgroup was detected by flow cytometry. The transwell co-culture system was applied to investigate the interact of immune cells and leukemia cells. BSP was used for investigating the methylation level of FOXC1. Dual luciferase report system was employed to detect the transcription level of target genes.Results: High throughput sequencing screening identified that FOXC1 H446HG was participating in the differentiation of Treg in marrow. FOXC1 H446HG could induced the promotion of Treg/CTL shift in immune microenvironment, causing the abnormal proliferation of leukemia cells in vitro and in vivo. CpG islands formed by insertion mutation led to an abnormal increase in exon methylation and associated with the suppression of FOXC1. Decreased FOXC1 could attenuated the transcription of HDAC1 resulting in the activation of KLF10 through promoting the H3K27 acetylation in the promoter region.Conclusions: The de novo inserting mutation in FOXC1 induced a suppression of FOXC1 promoting the Treg/CTL shift in ALL immune microenvironment. The FOXC1 H446HG mutation might be a potential therapeutic target for ALL in future.