Department of Internal Medicine and Clinical Research, University Hospital Bern, University of Bern, Bern, Switzerland.
Oncogene. 2010 Feb 18;29(7):1062-72. doi: 10.1038/onc.2009.371. Epub 2009 Dec 7.
The majority of patients with acute myeloid leukemia (AML) still die of their disease, and novel therapeutic concepts are needed. Timely expression of the hematopoietic master regulator PU.1 is crucial for normal development of myeloid and lymphoid cells. Targeted disruption of an upstream regulatory element (URE) located several kb upstream in the PU.1 promoter decreases PU.1 expression thereby inducing AML in mice. In addition, suppression of PU.1 has been observed in specific subtypes of human AML. Here, we identified nuclear factor-kappaB (NF-kappaB) to activate PU.1 expression through a novel site within the URE. We found sequence variations of this particular NF-kappaB site in 4 of 120 AML patients. These variant NF-kappaB sequences failed to mediate activation of PU.1. Moreover, the synergistic activation of PU.1 together with CEBPB through these variant sequences was also lost. Finally, AML patients with such variant sequences had suppressed PU.1 mRNA expression. This study suggests that changes of a single base pair in a distal element critically affect the regulation of the tumor suppressor gene PU.1 thereby contributing to the development of AML.
大多数急性髓细胞白血病 (AML) 患者仍死于该疾病，因此需要新的治疗概念。造血主调控因子 PU.1 的及时表达对于髓系和淋巴系细胞的正常发育至关重要。靶向破坏位于 PU.1 启动子上游几个 kb 的上游调节元件 (URE) 会降低 PU.1 的表达，从而在小鼠中诱导 AML。此外，在特定类型的人类 AML 中观察到 PU.1 的抑制。在这里，我们确定了核因子-κB (NF-κB) 通过 URE 内的一个新位点激活 PU.1 表达。我们在 120 名 AML 患者中的 4 名中发现了该特定 NF-κB 位点的序列变异。这些变体 NF-κB 序列未能介导 PU.1 的激活。此外，通过这些变体序列，PU.1 与 CEBPB 的协同激活也丢失了。最后，具有这种变体序列的 AML 患者的 PU.1 mRNA 表达受到抑制。这项研究表明，远端元件中单碱基对的变化会严重影响肿瘤抑制基因 PU.1 的调控，从而导致 AML 的发生。
