Salek-Ardakani Samira, Smooha Gil, de Boer Jasper, Sebire Neil J, Morrow Michelle, Rainis Liat, Lee Sandy, Williams Owen, Izraeli Shai, Brady Hugh J M
Molecular Haematology and Cancer Biology Unit, University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, United Kingdom.
Cancer Res. 2009 Jun 1;69(11):4665-73. doi: 10.1158/0008-5472.CAN-09-0075.
Ets-related gene (ERG) is a member of the ETS transcription factor gene family located on Hsa21. ERG is known to have a crucial role in establishing definitive hematopoiesis and is required for normal megakaryopoiesis. Truncated forms of ERG are associated with multiple cancers such as Ewing's sarcoma, prostate cancer, and leukemia as part of oncogenic fusion translocations. Increased expression of ERG is highly indicative of poor prognosis in acute myeloid leukemia and ERG is expressed in acute megakaryoblastic leukemia (AMKL); however, it is unclear if expression of ERG per se has a leukemogenic activity. We show that ectopic expression of ERG in fetal hematopoietic progenitors promotes megakaryopoiesis and that ERG alone acts as a potent oncogene in vivo leading to rapid onset of leukemia in mice. We observe that the endogenous ERG is required for the proliferation and maintenance of AMKL cell lines. ERG also strongly cooperates with the GATA1s mutated protein, found in Down syndrome AMKL, to immortalize megakaryocyte progenitors, suggesting that the additional copy of ERG in trisomy 21 may have a role in Down syndrome AMKL. These data suggest that ERG is a hematopoietic oncogene that may play a direct role in myeloid leukemia pathogenesis.
ETS相关基因（ERG）是位于人21号染色体（Hsa21）上的ETS转录因子基因家族的成员。已知ERG在确立定型造血过程中起关键作用，并且是正常巨核细胞生成所必需的。作为致癌融合易位的一部分，ERG的截短形式与多种癌症相关，如尤因肉瘤、前列腺癌和白血病。ERG表达增加高度提示急性髓系白血病预后不良，并且ERG在急性巨核细胞白血病（AMKL）中表达；然而，尚不清楚ERG本身的表达是否具有致白血病活性。我们发现，在胎儿造血祖细胞中异位表达ERG可促进巨核细胞生成，并且ERG单独在体内作为一种强效癌基因，可导致小鼠迅速发生白血病。我们观察到，内源性ERG是AMKL细胞系增殖和维持所必需的。ERG还与唐氏综合征AMKL中发现的GATA1s突变蛋白强烈协同作用，使巨核细胞祖细胞永生化，这表明21三体中额外的ERG拷贝可能在唐氏综合征AMKL中起作用。这些数据表明，ERG是一种造血癌基因，可能在髓系白血病发病机制中起直接作用。
