RaRF 通过将 RAR 隔离到核仁并调节白血病细胞中的 MCL1 来赋予 RA 抗性。
RaRF confers RA resistance by sequestering RAR to the nucleolus and regulating MCL1 in leukemia cells.
机构信息
Department of Integrative Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul, Korea.
Department of Molecular Biology, Dankook University, Cheonan-si, Chungnam, Korea.
出版信息
Oncogene. 2018 Jan 18;37(3):352-362. doi: 10.1038/onc.2017.329. Epub 2017 Sep 25.
Retinoic acid (RA) has broad clinical applications for the treatment of various cancers, particularly acute promyelocytic leukemia. However, RA-based therapy is limited by relapse in patients associated with RA resistance, the mechanism of which is poorly understood. Here, we suggest a new molecular mechanism of RA resistance by a repressor, named RA resistance factor (RaRF). RaRF suppressed transcriptional activity of the RA receptor (RAR) by directly interacting with and sequestering RAR to the nucleolus in response to RA. RaRF was highly expressed in RA-resistant leukemia cells and its expression was strongly correlated with RA sensitivity. MCL1 was upregulated by RA treatment upon RaRF depletion, accompanying leukemic myeloblast differentiation, which is negatively regulated by ectopic RaRF expression. Collectively, we propose that RaRF may be a factor in the resistance mechanism and thus a potential target for leukemia therapy using RA.
视黄酸（RA）在治疗各种癌症，特别是急性早幼粒细胞白血病方面具有广泛的临床应用。然而，基于 RA 的治疗受到与 RA 耐药相关的患者复发的限制，其机制尚不清楚。在这里，我们通过一种称为 RA 耐药因子（RaRF）的抑制剂提出了 RA 耐药的一个新的分子机制。RaRF 通过直接与 RA 受体（RAR）相互作用并将 RAR 隔离到核仁中来抑制 RA 的转录活性。RaRF 在 RA 耐药白血病细胞中高表达，其表达与 RA 敏感性强烈相关。在 RaRF 耗尽时，MCL1 被 RA 处理上调，伴随白血病髓样母细胞分化，而异位 RaRF 表达则负调控。总的来说，我们提出 RaRF 可能是耐药机制中的一个因素，因此可能成为使用 RA 治疗白血病的潜在靶点。
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