Sox4 is a key oncogenic target in C/EBPa mutant Acute Myeloid Leukemia

Mutation or epigenetic silencing of the transcription factor C/EBPa is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBPa whereby its expression is inversely correlated with C/EBPa activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine mutant C/EBPa AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPa inactivation contributes to the development of leukemias with a distinct LIC phenotype. A ChIP-seq sample of C/EBPa in Macrophages is used in this study

在约10%的急性髓系白血病（acute myeloid leukemia, AML）患者中，可检测到转录因子C/EBPa发生突变或表观遗传沉默。两类异常均呈现出一致的全局基因表达特征，但其介导白血病发生的下游调控靶点仍未明确。本研究鉴定出Sox4为C/EBPa的直接靶基因，其表达水平与C/EBPa的活性呈负相关。下调Sox4的表达可消除白血病细胞自我更新能力的异常增强，并恢复其分化能力。来自Sox4过表达模型与小鼠突变型C/EBPa AML模型的白血病起始细胞（leukemia initiating cells, LICs）的基因表达谱聚为一类，但与其他亚型的AML存在显著差异。本研究数据证实，因C/EBPa失活所导致的Sox4过表达，可促成具有独特白血病起始细胞表型的白血病发生。本研究使用了巨噬细胞中C/EBPa的染色质免疫共沉淀测序（ChIP-seq）样本。