Department of Hematology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510230, China.
Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou 510230, China.
Br J Cancer. 2018 Feb 6;118(3):405-415. doi: 10.1038/bjc.2017.403. Epub 2018 Jan 2.
High-mobility group AT-hook 2 (HMGA2) may serve as an architectural transcription factor, and it can regulate a range of normal biological processes including proliferation and differentiation. Upregulation of HMGA2 expression is correlated to the undifferentiated phenotype of immature leukaemic cells. However, the underlying mechanism of HMGA2-dependent myeloid differentiation blockage in leukaemia is unknown.
To reveal the role and mechanism of HMGA2 in differentiation arrest of myeloid leukaemia cells, the quantitative expression of HMGA2 and homeobox A9 (HOXA9) was analysed by real-time PCR (qRT-PCR). The regulatory function of HMGA2 in blockage of differentiation in human myeloid leukaemia was investigated through in vitro assays (XTT assay, May-Grünwald-Giemsa, flow cytometry analysis and western blot).
We found that the expression of HMGA2 and HOXA9 was reduced during the process of granulo-monocytic maturation of acute myeloid leukaemia (AML) cells, knockdown of HMGA2 promotes terminal (granulocytic and monocytic) differentiation of myeloid leukaemia primary blasts and cell lines, and HOXA9 was significantly downregulated in leukaemic cells with knockdown of HMGA2. Downregulation of HOXA9 in myeloid leukaemia cells led to increased differentiation capacity in vitro.
Our data suggest that increased expression of HMGA2 represents a possible new mechanism of myeloid differentiation blockage of leukaemia. Aberrant expression of HMGA2 may enhance HOXA9-dependent leukaemogenesis and myeloid leukaemia phenotype. Disturbance of the HMGA2-HOXA9 pathway is probably a therapeutic strategy in myeloid leukaemia.
高迁移率族蛋白 A2（HMGA2）可能作为一种结构转录因子，调节包括增殖和分化在内的一系列正常生物学过程。HMGA2 表达的上调与未分化的幼稚白血病细胞表型相关。然而，HMGA2 依赖性髓系白血病细胞分化阻滞的潜在机制尚不清楚。
为了揭示 HMGA2 在髓系白血病细胞分化阻滞中的作用和机制，通过实时 PCR（qRT-PCR）分析 HMGA2 和同源盒 A9（HOXA9）的定量表达。通过体外实验（XTT 测定、迈-格-吉染色、流式细胞术分析和 Western blot）研究 HMGA2 在阻断人髓系白血病分化中的调节功能。
我们发现 HMGA2 和 HOXA9 的表达在急性髓系白血病（AML）细胞的粒细胞单核细胞成熟过程中降低，HMGA2 的敲低促进髓系白血病原代细胞和细胞系的终末（粒细胞和单核细胞）分化，并且在 HMGA2 敲低的白血病细胞中 HOXA9 明显下调。HOXA9 在髓系白血病细胞中的下调导致体外分化能力增加。
我们的数据表明，HMGA2 的高表达代表了白血病髓系分化阻滞的一种新的可能机制。HMGA2 的异常表达可能增强 HOXA9 依赖性白血病发生和髓系白血病表型。干扰 HMGA2-HOXA9 通路可能是髓系白血病的一种治疗策略。
