Department of Genetics, University Erlangen, Erlangen, Germany.
Blood. 2010 Apr 8;115(14):2910-8. doi: 10.1182/blood-2009-04-216606. Epub 2010 Feb 3.
HOX homeobox genes are important regulators of normal and malignant hematopoiesis. Abdominal-type HOXA genes like HOXA9 are highly leukemogenic. However, little is known about transformation by anterior HOXA genes. Here we performed a comprehensive assessment of the oncogenic potential of every HOXA gene in primary hematopoietic cells. With exception of HOXA2 and HOXA5, all HOXA genes caused a block or delay of hematopoietic differentiation and cooperated with Meis1. No evidence for the alleged tumor-suppressor function of HOXA5 could be found. Whereas all active HOXA genes immortalized mixed granulocytic/monocytic populations, HOXA13 preferentially specified monocytoid development. The anterior HOXA genes HOXA1, HOXA4, and HOXA6 transformed cells, generating permanent cell lines, although they did so less potently than HOXA9. Upon transplantation these lines induced myeloproliferation and acute myeloid leukemia in recipient animals. Kinetic studies with inducible HOX derivatives demonstrated that anterior HOXA genes autonomously contributed to cellular transformation. This function was not mediated by endogenous Hoxa9, which was persistently expressed in cells transformed by anterior HOX genes. In summary our results demonstrate a hitherto unexpected role of anterior HOXA genes in hematopoietic malignancy.
HOX 同源盒基因是正常和恶性造血的重要调节因子。像 HOXA9 这样的腹部型 HOXA 基因具有高度的白血病发生能力。然而，对于前 HOXA 基因的转化作用知之甚少。在这里，我们对每个 HOXA 基因在原代造血细胞中的致癌潜能进行了全面评估。除了 HOXA2 和 HOXA5 之外，所有的 HOXA 基因都导致造血分化的阻滞或延迟，并与 Meis1 合作。没有发现 HOXA5 据称的肿瘤抑制功能的证据。虽然所有有活性的 HOXA 基因都能使混合粒细胞/单核细胞群体永生化，但 HOXA13 更倾向于指定单核细胞的发育。前 HOXA 基因 HOXA1、HOXA4 和 HOXA6 转化细胞，产生永久性细胞系，尽管它们的转化能力不如 HOXA9 强。这些细胞系在移植后可诱导受者动物发生骨髓增生和急性髓系白血病。用诱导型 HOX 衍生物进行的动力学研究表明，前 HOXA 基因自主地参与了细胞转化。这一功能不是由内源性 Hoxa9 介导的，HOXA9 在被前 HOXA 基因转化的细胞中持续表达。总之，我们的研究结果表明，前 HOXA 基因在造血恶性肿瘤中具有迄今为止尚未被认识到的作用。
