Activation of the Lysosome-Associated Membrane Protein LAMP5 by DOT1L Serves as a Bodyguard for MLL Fusion Oncoproteins to Evade Degradation in Leukemia
Activation of the Lysosome-Associated Membrane Protein LAMP5 by DOT1L Serves as a Bodyguard for MLL Fusion Oncoproteins to Evade Degradation in Leukemia
复制标题
DOT1L 激活溶酶体相关膜蛋白 LAMP5 作为 MLL 融合癌蛋白的保镖，避免白血病中的降解
DOI：
10.1158/1078-0432.ccr-18-1474
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发表时间：
2019
影响因子：
11.5
通讯作者：
Chen Yue-Qin
中科院分区：
文献类型：
--
作者：
Wang Wen-Tao;Han Cai;Sun Yu-Meng;Chen Zhen-Hua;Fang Ke;Huang Wei;Sun Lin-Yu;Zeng Zhan-Cheng;Luo Xue-Qun;Chen Yue-Qin
目的：尽管对混合系白血病（MLL白血病）进行了许多尝试，但对这种疾病的有效治疗仍然有限。我们鉴定了一种溶酶体相关膜蛋白（LAMP）家族成员LAMP 5，其在MLL白血病患者中特异性高表达。该研究的目的是证明LAMP 5在疾病中的功能相关性和临床价值。实验设计：我们首先招募了一个大型白血病患者队列，以验证LAMP 5表达并评估其临床价值。然后，我们进行了体外和体内实验，以研究LAMP 5在MLL白血病进展或维持中的功能相关性。结果：LAMP 5被证实在MLL白血病患者中特异性和高表达，并与不良结局相关。功能研究表明，LAMP 5是一种新的自噬抑制因子，可保护MLL融合蛋白免于自噬降解。在动物模型和原代细胞中，特异性靶向LAMP 5显著促进MLL融合蛋白的降解并抑制MLL白血病进展。我们进一步揭示了LAMP 5是H3 K79组蛋白甲基转移酶DOT 1 L的直接靶点。用DOT 1 L抑制剂下调LAMP 5增强了MLL癌蛋白的选择性自噬降解并延长了体内生存期;当DOT 1 L抑制剂与LAMP 5敲低结合时，这一观察结果尤其重要。结论：这项研究表明，LAMP 5作为MLL融合的“保镖”，以避免降解，并且是第一个将H3 K79甲基化与自噬调控联系起来的，突出了LAMP 5作为MLL白血病治疗靶点的潜力。
Purpose: Despite many attempts to understand mixed-lineage leukemia (MLL leukemia), effective therapies for this disease remain limited. We identified a lysosome-associated membrane protein (LAMP) family member, LAMP5, that is specifically and highly expressed in patients with MLL leukemia. The purpose of the study was to demonstrate the functional relevance and clinical value of LAMP5 in the disease. Experimental Design: We first recruited a large cohort of leukemia patients to validate LAMP5 expression and evaluate its clinical value. We then performed in vitro and in vivo experiments to investigate the functional relevance of LAMP5 in MLL leukemia progression or maintenance. Results: LAMP5 was validated as being specifically and highly expressed in patients with MLL leukemia and was associated with a poor outcome. Functional studies showed that LAMP5 is a novel autophagic suppressor and protects MLL fusion proteins from autophagic degradation. Specifically targeting LAMP5 significantly promoted degradation of MLL fusion proteins and inhibited MLL leukemia progression in both an animal model and primary cells. We further revealed that LAMP5 is a direct target of the H3K79 histone methyltransferase DOT1L. Downregulating LAMP5 with a DOT1L inhibitor enhanced the selective autophagic degradation of MLL oncoproteins and extended survival in vivo; this observation was especially significant when combining DOT1L inhibitors with LAMP5 knockdown. Conclusions: This study demonstrates that LAMP5 serves as a “bodyguard” for MLL fusions to evade degradation and is the first to link H3K79 methylation to autophagy regulation, highlighting the potential of LAMP5 as a therapeutic target for MLL leukemia.