Department of Genetics, University of Erlangen, Erlangen, Germany.
Leukemia. 2015 Apr;29(4):901-8. doi: 10.1038/leu.2014.287. Epub 2014 Sep 25.
HOX homeobox proteins are key oncogenic drivers in hematopoietic malignancies. Here we demonstrate that HOXA1, HOXA6 and predominantly HOXA9 are able to induce the production of insulin-like growth factor 1 (Igf1). In chromatin immunoprecipitations, HOXA9 bound directly to the putative promoter and a DNase-hypersensitive region in the first intron of the Igf1 gene. Transcription rates of the Igf1 gene paralleled HOXA9 activity. Primary cells transformed by HOXA9 expressed functional Igf1 receptors and activated the protein kinase Akt in response to Igf1 stimulation, suggesting the existence of an autocrine signaling loop. Genomic deletion of the Igf1 gene by Cre-mediated recombination increased sensitivity toward apoptosis after serum starvation. In addition, the leukemogenic potential of Igf1-negative, HOXA9-transformed cells was impaired, leading to a significant delay in disease development on transplantation into recipient animals.
HOX 同源盒蛋白是造血系统恶性肿瘤的关键致癌驱动因子。在这里，我们证明 HOXA1、HOXA6 和主要的 HOXA9 能够诱导胰岛素样生长因子 1（Igf1）的产生。在染色质免疫沉淀中，HOXA9 直接结合到 Igf1 基因第一个内含子的假定启动子和 DNA 酶超敏区域。Igf1 基因的转录率与 HOXA9 的活性平行。被 HOXA9 转化的原代细胞表达功能性 Igf1 受体，并在受到 Igf1 刺激时激活蛋白激酶 Akt，表明存在自分泌信号环路。通过 Cre 介导的重组对 Igf1 基因进行基因组缺失增加了血清饥饿后细胞凋亡的敏感性。此外，Igf1 阴性、HOXA9 转化细胞的白血病发生潜能受损，导致在移植到受体动物后疾病发展明显延迟。
