DNAJC10调控急性髓系白血病干细胞多能性的作用及分子机制

Leukemia stem cells (LSCs) are considered as the source of leukemogenesis and development, are also the root cause for the treatment failure and relapse. Understanding how LSCs respond to stress will contribute to identification of novel molecular targets for treating acute myeloid leukemia (AML). However, how AML cells protect themselves during stress remains poorly understood. For the first time, we found that Endoplasmic Reticulum Resident Protein DNAJC10 was highly expressed in LSCs. Importantly, the DNAJC10 expression level negatively correlates with the survival of AML patients. Also, blocked DNAJC10 could induced endoplasmic reticulum stress signaling PERK-eIF2α-ATF4-CHOP activation, and induced AML cells apoptosis. Here we propose to test the hypothesis that DNAJC10 protects AML stem cells in stressful environment. We will determine the regulatory role of DNAJC10 in AML development and identify its signal transduction mechanisms. We believe that our study will elucidate the function of DNAJC10 in protecting AML LSCs during stress, and form the basis for the development of novel AML therapeutics.

白血病干细胞是造成白血病发生、发展和复发的根本原因。内质网应激与肿瘤发生发展密切相关。研究白血病干细胞在应激状态下如何自我保护，有助于寻找抑制白血病干细胞活性的分子靶标。然而，白血病干细胞在应激状态下的反应及分子机制迄今不详。本项目首次发现：DNAJC10在急性髓系白血病干细胞高表达；DNAJC10表达水平与急性髓系白血病患者生存时间呈负相关；且敲降DNAJC10可激活内质网应激凋亡通路PERK-ATF4，诱导急性髓系白血病细胞系凋亡。推测，DNAJC10可能通过调节内质网凋亡和存活通路的平衡，保护应激状态下的白血病干细胞。因此，本项目拟深入研究DNAJC10在调控急性髓系白血病干细胞多能性和病程演进中的作用，并阐明其分子机制。这些研究有助于揭示应激时白血病干细胞的自我保护机制，具有重要的理论价值；同时，可以为寻找治疗白血病的分子靶标奠定理论基础，具有潜在应用价值。

白血病干细胞是造成白血病发生、发展和复发的根本原因。内质网应激与肿瘤发生发展密切相关。研究白血病干细胞在应激状态下如何自我保护，有助于寻找抑制白血病干细胞活性的分子靶标。然而，白血病干细胞在应激状态下的反应及分子机制迄今不详。我们推测，内质网驻留蛋白DNAJC10可能通过调节内质网凋亡和存活通路的平衡，保护应激状态下的白血病干细胞。因此，本项目深入研究了DNAJC10在调控AML-SC多能性和病程演进中的作用，并阐明了相关分子机制。本研究发现：① DNAJC10在AML患者高表达，且与患者生存周期呈显著负相关。② DNAJC10在体内促进AML的发展演进；抑制DNAJC10可以减缓AML发展，延长AML模型小鼠生存时间；③ DNAJC10维持AML-SC多能性，抑制DNAJC10可显著抑制AML-SC的自我更新和生长。④ DNAJC10通过调节内质网应激维持AML-SC多能性并促AML的体内发展。这些工作提示，DNAJC10可能是AML治疗的潜在靶点。并且，抑制DNAJC10具有抑制AML-SC多能性的作用，从而达到治疗甚至治愈AML的效果。