State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Cell Mol Med. 2018 Dec;22(12):6275-6284. doi: 10.1111/jcmm.13917. Epub 2018 Oct 15.
The PML-RARα fusion gene, generated by the t(15;17) chromosome translocation, is regarded as the initiating factor of acute promyelocytic leukaemia (APL). In addition to the well-known effects on blocking myeloid differentiation at the promyelocytic stage, promyelocytic leukaemia-retinoic acid receptor α (PML-RARα) has also been reported to interfere with multiple differentiation processes, including erythroid differentiation. However, the detailed molecular mechanism by which PML-RARα impairs erythropoiesis has not yet been fully addressed. By chromatin immunoprecipitation-PCR assay, we found that PML-RARα bound to the distal promoter region of LMO2 (LIM-only protein 2), a critical erythroid-specific transcription factor. Luciferase reporter assays and qRT-PCR results demonstrated that PML-RARα down-regulated the expression of the LMO2 distal transcript through transrepressing its promoter activity. Analysis of gene expression profiling data from large cohorts of acute myeloid leukaemia (AML) patients confirmed that LMO2 expressed at a markedly lower level in APL patients in comparison to non-APL AML patients. Further flow cytometry analysis demonstrated that PML-RARα inhibited erythropoietin-induced erythroid differentiation by down-regulating LMO2 expression. Our findings reveal a previously unidentified mechanism, by which PML-RARα interferes with erythropoiesis through directly targeting and transrepressing LMO2 expression in the development of APL.
PML-RARα 融合基因由 t(15;17)染色体易位产生，被认为是急性早幼粒细胞白血病（APL）的起始因素。除了众所周知的在早幼粒细胞阶段阻断髓系分化的作用外，早幼粒细胞白血病-维甲酸受体α（PML-RARα）还被报道干扰多个分化过程，包括红细胞分化。然而，PML-RARα 如何损害红细胞生成的详细分子机制尚未完全阐明。通过染色质免疫沉淀-PCR 分析，我们发现 PML-RARα 与 LMO2（LIM 仅蛋白 2）的远端启动子区域结合，LMO2 是一种关键的红细胞特异性转录因子。荧光素酶报告基因检测和 qRT-PCR 结果表明，PML-RARα 通过反式抑制其启动子活性下调 LMO2 远端转录本的表达。对大量急性髓系白血病（AML）患者的基因表达谱数据的分析证实，与非 APL AML 患者相比，APL 患者的 LMO2 表达水平明显降低。进一步的流式细胞术分析表明，PML-RARα 通过下调 LMO2 表达抑制促红细胞生成素诱导的红细胞分化。我们的研究结果揭示了一种以前未被识别的机制，即 PML-RARα 通过直接靶向和反式抑制 LMO2 在 APL 发育过程中的表达，干扰红细胞生成。
