Daniele Giulia, Simonetti Giorgia, Fusilli Caterina, Iacobucci Ilaria, Lonoce Angelo, Palazzo Antonio, Lomiento Mariana, Mammoli Fabiana, Marsano Renè Massimiliano, Marasco Elena, Mantovani Vilma, Quentmeier Hilmar, Drexler Hans G, Ding Jie, Palumbo Orazio, Carella Massimo, Nadarajah Niroshan, Perricone Margherita, Ottaviani Emanuela, Baldazzi Carmen, Testoni Nicoletta, Papayannidis Cristina, Ferrari Sergio, Mazza Tommaso, Martinelli Giovanni, Storlazzi Clelia Tiziana
Department of Biology, University of Bari "A. Moro", Italy.
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy.
Haematologica. 2017 Jul;102(7):1204-1214. doi: 10.3324/haematol.2016.163022. Epub 2017 Apr 14.
We here describe a leukemogenic role of the homeobox gene , activated by epigenetic modifications in acute myeloid leukemia (AML). We found the ectopic activation of in a leukemia patient harboring a t(7;10)(p22;p14) translocation, in 22 of 61 of additional cases [a total of 23 positive patients out of 62 (37.1%)], and in 6 of 75 (8%) of AML cell lines. is embedded within a low-methylation region (canyon) and encodes for a transcription factor involved in somitogenesis and neurogenesis, with specific expression in the eye, brain, and kidney. expression turned out to be associated, and significantly correlated, with DNA methylation increase at its canyon borders based on data in our patients and in archived data of patients from The Cancer Genome Atlas. -positive and -negative patients displayed significant differences in their gene expression profiles. An enrichment of genes involved in cell proliferation and differentiation, such as and , was revealed. Similar results were obtained in -transduced CD34 cells, associated with low proliferation and differentiation arrest. Accordingly, we showed that expression characterizes leukemia cells at their early stage of differentiation, mainly M2 and M3 subtypes carrying wild-type We also observed that expression significantly associates with an increased frequency of acute promyelocytic leukemia with and AML with t(8;21)(q22;q22.1); classes, according to the World Health Organization disease classification. In summary, our findings suggest a novel leukemogenic role of , associated with epigenetic modifications and with impaired cell proliferation and differentiation in AML.
我们在此描述了一个同源盒基因在急性髓系白血病（AML）中通过表观遗传修饰激活后的致白血病作用。我们在一名患有t(7;10)(p22;p14)易位的白血病患者中发现了该基因的异位激活，在另外61例中的22例中也发现了这种激活（62例中共有23例阳性患者，占37.1%），并且在75株AML细胞系中的7株（8%）中也发现了该基因的激活。该基因位于一个低甲基化区域（峡谷）内，编码一种参与体节发生和神经发生的转录因子，在眼睛、大脑和肾脏中有特异性表达。根据我们患者的数据以及来自癌症基因组图谱的患者存档数据，该基因的表达结果与峡谷边界处DNA甲基化增加相关且显著相关。该基因阳性和阴性患者在基因表达谱上存在显著差异。揭示了参与细胞增殖和分化的基因富集，如某些基因。在转导该基因的CD34细胞中也获得了类似结果，与低增殖和分化停滞相关。因此，我们表明该基因的表达表征了白血病细胞分化的早期阶段，主要是携带野生型该基因的M2和M3亚型。我们还观察到，根据世界卫生组织疾病分类，该基因的表达与伴有特定异常的急性早幼粒细胞白血病和伴有t(8;21)(q22;q22.1)的AML的频率增加显著相关。总之，我们的研究结果表明该基因具有一种新的致白血病作用，与表观遗传修饰以及AML中细胞增殖和分化受损有关。
