最近的大规模测序研究揭示，SWI/SNF复合物是实体肿瘤中最常见的功能性改变之一。然而，SWI/SNF在急性髓系白血病中的作用尚不清楚。迄今为止，SWI/SNF复合物被认为是AML的致癌基因，或者至少是支持白血病发生的必要因素。然而，AML中SWI/SNF基因的突变模式与肿瘤抑制基因的作用相一致。本研究探讨了SWI/SNF亚基BCL7A在淋巴瘤中常发生突变，但其在急性髓系恶性肿瘤中的作用尚不明确。 采用数据挖掘和生物信息学方法研究BCL7A的突变状态以及BCL7A表达和启动子高甲基化之间的相关性。采用甲基化特异性PCR、亚硫酸氢盐测序和5-aza-2'-脱氧胞苷治疗试验确定BCL7A表达是否因启动子高甲基化而被抑制。进行BCL7A表达恢复后的细胞竞争试验，以评估BCL7A在AML细胞株模型中的作用。进行差异表达分析，确定BCL7A表达恢复后的途径和基因的变化。通过体内荧光成像比较BCL7A表达与非表达的小鼠异种移植瘤之间的肿瘤生长，以确定BCL7A在肿瘤发展中的作用。 BCL7A表达与三个外部队列（TCGA-LAML（N = 160）、TARGET-AML（N = 188）和Glass等人（2017）（N = 111））的启动子甲基化成反比例关系。AML衍生的细胞系NB4通过启动子高甲基化来沉默BCL7A表达。AML细胞中异位表达BCL7A降低了它们与对照细胞的竞争能力。另外，异位表达BCL7A在NB4小鼠异种移植模型中减少了肿瘤生长。此外，差异表达分析发现，BCL7A表达恢复改变了细胞周期途径，并显著修改了基因的表达，如HMGCS1、H1-0和IRF7，这有助于解释它在AML中的肿瘤抑制作用。 BCL7A表达在AML中受到启动子甲基化的抑制。此外，恢复BCL7A表达在AML细胞系和异种移植模型中具有抑瘤作用。©2023.作者.

Recent massive sequencing studies have revealed that SWI/SNF complexes are among the most frequently altered functional entities in solid tumors. However, the role of SWI/SNF in acute myeloid leukemia is poorly understood. To date, SWI/SNF complexes are thought to be oncogenic in AML or, at least, necessary to support leukemogenesis. However, mutation patterns in SWI/SNF genes in AML are consistent with a tumor suppressor role. Here, we study the SWI/SNF subunit BCL7A, which has been found to be recurrently mutated in lymphomas, but whose role in acute myeloid malignancies is currently unknown.Data mining and bioinformatic approaches were used to study the mutational status of BCL7A and the correlation between BCL7A expression and promoter hypermethylation. Methylation-specific PCR, bisulfite sequencing, and 5-aza-2'-deoxycytidine treatment assays were used to determine if BCL7A expression was silenced due to promoter hypermethylation. Cell competition assays after BCL7A expression restoration were used to assess the role of BCL7A in AML cell line models. Differential expression analysis was performed to determine pathways and genes altered after BCL7A expression restoration. To establish the role of BCL7A in tumor development in vivo, tumor growth was compared between BCL7A-expressing and non-expressing mouse xenografts using in vivo fluorescence imaging.BCL7A expression was inversely correlated with promoter methylation in three external cohorts: TCGA-LAML (N = 160), TARGET-AML (N = 188), and Glass et al. (2017) (N = 111). The AML-derived cell line NB4 silenced the BCL7A expression via promoter hypermethylation. Ectopic BCL7A expression in AML cells decreased their competitive ability compared to control cells. Additionally, restoration of BCL7A expression reduced tumor growth in an NB4 mouse xenograft model. Also, differential expression analysis found that BCL7A restoration altered cell cycle pathways and modified significantly the expression of genes like HMGCS1, H1-0, and IRF7 which can help to explain its tumor suppressor role in AML.BCL7A expression is silenced in AML by promoter methylation. In addition, restoration of BCL7A expression exerts tumor suppressor activity in AML cell lines and xenograft models.© 2023. The Author(s).