Stroopinsky Dina, Rajabi Hasan, Nahas Myrna, Rosenblatt Jacalyn, Rahimian Maryam, Pyzer Athalia, Tagde Ashujit, Kharbanda Akriti, Jain Salvia, Kufe Turner, Leaf Rebecca K, Anastasiadou Eleni, Bar-Natan Michal, Orr Shira, Coll Maxwell D, Palmer Kristen, Ephraim Adam, Cole Leandra, Washington Abigail, Kufe Donald, Avigan David
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Harvard Medical School, Dana Farber Cancer Institute, Boston, MA, USA.
J Cell Mol Med. 2018 Aug;22(8):3887-3898. doi: 10.1111/jcmm.13662. Epub 2018 May 15.
Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with an unmet need for improved therapies. Responses to standard cytotoxic therapy in AML are often transient because of the emergence of chemotherapy-resistant disease. The MUC1-C oncoprotein governs critical pathways of tumorigenesis, including self-renewal and survival, and is aberrantly expressed in AML blasts and leukaemia stem cells (LSCs). However, a role for MUC1-C in linking leukaemogenesis and resistance to treatment has not been described. In this study, we demonstrate that MUC1-C overexpression is associated with increased leukaemia initiating capacity in an NSG mouse model. In concert with those results, MUC1-C silencing in multiple AML cell lines significantly reduced the establishment of AML in vivo. In addition, targeting MUC1-C with silencing or pharmacologic inhibition with GO-203 led to a decrease in active β-catenin levels and, in-turn, down-regulation of survivin, a critical mediator of leukaemia cell survival. Targeting MUC1-C was also associated with increased sensitivity of AML cells to Cytarabine (Ara-C) treatment by a survivin-dependent mechanism. Notably, low MUC1 and survivin gene expression were associated with better clinical outcomes in patients with AML. These findings emphasize the importance of MUC1-C to myeloid leukaemogenesis and resistance to treatment by driving survivin expression. Our findings also highlight the potential translational relevance of combining GO-203 with Ara-C for the treatment of patients with AML.
急性髓系白血病（AML）是一种侵袭性血液系统恶性肿瘤，对改进治疗方法存在未满足的需求。由于化疗耐药性疾病的出现，AML对标准细胞毒性疗法的反应往往是短暂的。MUC1-C癌蛋白控制着肿瘤发生的关键途径，包括自我更新和存活，并且在AML原始细胞和白血病干细胞（LSCs）中异常表达。然而，MUC1-C在白血病发生与治疗耐药性之间的联系尚未见报道。在本研究中，我们证明在NSG小鼠模型中，MUC1-C过表达与白血病起始能力增强相关。与这些结果一致，在多个AML细胞系中沉默MUC1-C显著降低了体内AML的形成。此外，用GO-203进行沉默或药物抑制靶向MUC1-C导致活性β-连环蛋白水平降低，进而下调存活素，存活素是白血病细胞存活的关键调节因子。靶向MUC1-C还通过依赖存活素的机制使AML细胞对阿糖胞苷（Ara-C）治疗的敏感性增加。值得注意的是，低MUC1和存活素基因表达与AML患者更好的临床结果相关。这些发现强调了MUC1-C通过驱动存活素表达在髓系白血病发生和治疗耐药性中的重要性。我们的发现还突出了将GO-203与Ara-C联合用于治疗AML患者的潜在转化相关性。
