Shu Yi, Zhou Xiaoyan, Qi Xinkun, Liu Shan, Li Kang, Tan Junjie, Liu Zhidai, Yu Jie, Zhang Penghui, Zou Lin
Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China; Key Laboratory of Pediatrics in Chongqing, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Chongqing 400014, China; Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Medical University, Chongqing 400014, China; Chongqing Stem Cell Therapy Engineering Technical Research Center, Children's Hospital, Chongqing Medical University, Chongqing 400014, China.
Cancer Lett. 2015 Feb 1;357(1):170-178. doi: 10.1016/j.canlet.2014.11.025. Epub 2014 Nov 15.
The self-renewal ability of the leukemia initiating cell-enriched subpopulation is critical for leukemia initiation and maintenance. However, the regulation of leukemia initiating cells for the leukemia progression is poorly understood. In this study, we observed that β-Arrestin1, a multiple-function protein, is elevated in leukemia initiating cells-enriched fraction from B-lineage acute lymphoblastic leukemia patients. The loss of β-Arrestin1 in leukemia initiating cells-enriched fraction attenuates its self-renewal capacity both in vitro and in vivo. Further experiments showed that the mRNA expression level of β-Arrestin1 is negatively correlated with that of PTEN in leukemia initiating cells-enriched fraction. Moreover, DNA methylation of the PTEN promoter region, the activity and expression of DNMTs were enhanced in the leukemia initiating cells-enriched fraction. The inhibition of DNMT1 activity impaired the self-renewal and increased expression of PTEN of leukemia initiating cells-enriched fraction. In addition, depletion of β-Arrestin1 significantly decreased DNMT1 activity and PTEN methylation, and consistently increased PTEN expression in leukemia initiating cells-enriched fraction. Our study reveals a novel function of β-Arrestin1 in the regulation of the self-renewal of leukemia initiating cells-enriched fraction from B-lineage acute lymphoblastic leukemia patients related to DNMT1 activity, indicating that β-Arrestin1 is a potential therapeutic target in B-lineage acute lymphoblastic leukemia.
富含白血病起始细胞的亚群的自我更新能力对于白血病的起始和维持至关重要。然而，白血病起始细胞对白血病进展的调控仍知之甚少。在本研究中，我们观察到多功能蛋白β-抑制蛋白1在B系急性淋巴细胞白血病患者富含白血病起始细胞的组分中表达升高。在富含白血病起始细胞的组分中敲除β-抑制蛋白1会在体外和体内减弱其自我更新能力。进一步实验表明，在富含白血病起始细胞的组分中，β-抑制蛋白1的mRNA表达水平与PTEN的mRNA表达水平呈负相关。此外，在富含白血病起始细胞的组分中，PTEN启动子区域的DNA甲基化、DNA甲基转移酶的活性和表达均增强。抑制DNA甲基转移酶1的活性会损害富含白血病起始细胞的组分的自我更新能力并增加PTEN的表达。此外，敲除β-抑制蛋白1会显著降低富含白血病起始细胞的组分中的DNA甲基转移酶1活性和PTEN甲基化，并持续增加PTEN的表达。我们的研究揭示了β-抑制蛋白1在调控B系急性淋巴细胞白血病患者富含白血病起始细胞的组分的自我更新中的新功能，该功能与DNA甲基转移酶1的活性相关，表明β-抑制蛋白1是B系急性淋巴细胞白血病的一个潜在治疗靶点。
