Oben Karine Z, Gachuki Beth W, Alhakeem Sara S, McKenna Mary K, Liang Ying, St Clair Daret K, Rangnekar Vivek M, Bondada Subbarao
Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky, United States of America.
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, United States of America.
PLoS One. 2017 Jan 12;12(1):e0169767. doi: 10.1371/journal.pone.0169767. eCollection 2017.
An understanding of how each individual 5q chromosome critical deleted region (CDR) gene contributes to malignant transformation would foster the development of much needed targeted therapies for the treatment of therapy related myeloid neoplasms (t-MNs). Early Growth Response 1 (EGR1) is a key transcriptional regulator of myeloid differentiation located within the 5q chromosome CDR that has been shown to regulate HSC (hematopoietic stem cell) quiescence as well as the master regulator of apoptosis-p53. Since resistance to apoptosis is a hallmark of malignant transformation, we investigated the role of EGR1 in apoptosis of bone marrow cells; a cell population from which myeloid malignancies arise. We evaluated radiation induced apoptosis of Egr1+/+ and Egr1-/- bone marrow cells in vitro and in vivo. EGR1 is not required for radiation induced apoptosis of murine bone marrow cells. Neither p53 mRNA (messenger RNA) nor protein expression is regulated by EGR1 in these cells. Radiation induced apoptosis of bone marrow cells by double strand DNA breaks induced p53 activation. These results suggest EGR1 dependent signaling mechanisms do not contribute to aberrant apoptosis of malignant cells in myeloid malignancies.
了解5号染色体上每个关键缺失区域(CDR)的基因如何促成恶性转化,将推动开发治疗治疗相关髓系肿瘤(t-MNs)急需的靶向疗法。早期生长反应因子1(EGR1)是位于5号染色体CDR内的髓系分化关键转录调节因子,已被证明可调节造血干细胞(HSC)的静止以及凋亡的主要调节因子p53。由于对凋亡的抗性是恶性转化的一个标志,我们研究了EGR1在骨髓细胞凋亡中的作用;骨髓细胞是髓系恶性肿瘤产生的细胞群体。我们在体外和体内评估了辐射诱导的Egr1+/+和Egr1-/-骨髓细胞凋亡。EGR1并非小鼠骨髓细胞辐射诱导凋亡所必需。在这些细胞中,p53信使核糖核酸(mRNA)和蛋白质表达均不受EGR1调节。辐射通过双链DNA断裂诱导p53激活,从而诱导骨髓细胞凋亡。这些结果表明,EGR1依赖性信号传导机制对髓系恶性肿瘤中恶性细胞的异常凋亡没有作用。