肿瘤是威胁全人类健康的重大问题，尽管目前治疗已取得一定进展，但肿瘤复发、转移和耐药仍然是目前临床治疗面临的重大问题和待攻克的难关。压力应激蛋白TRIB3（Tribbles Homologue 3）包含Ser/Thr激酶结构域却无激酶的催化活性，其生物学功能通常主要依靠蛋白质-蛋白质相互作用实现。我们前期探索TRIB3在多种实体肿瘤和白血病中的作用和机制，发现在不同肿瘤中该蛋白通过与多种重要促癌蛋白相互作用，进而影响肿瘤细胞的代谢、增殖、干性等生物学功能。更为重要的是，这些蛋白相互作用参与或决定肿瘤细胞的恶性程度，促进包括白血病、结直肠癌、黑色素瘤、肝癌、肺癌、三阴性乳腺癌等多种肿瘤的发生发展。

急性早幼粒细胞白血病（APL）属于急性髓系白血病（AML）的M3型，该疾病主要由融合蛋白PML-RARa诱发。我们前期研究发现，TRIB3在APL样本中表达升高，高表达的TRIB3通过与PML-RARa相互作用，抑制其泛素化及降解，维持PML-RARa的稳定性来介导APL的发生和疾病进展。尽管在APL治疗中，使用全反式维甲酸（ATRA）与三氧化二砷（As₂O₃）联合治疗能显著提高其治愈率，但是一线药物在治疗过程中也会引发耐药、复发以及脂质代谢异常等问题。虽然APL患者在一线治疗过程中常出现脂代谢紊乱，但其脂代谢异常机制及初诊病人的脂质水平并不清楚。本论文第一部分基于APL治疗存在的临床问题，探索APL患者治疗前后脂质代谢异常的具体生物学机制。通过回顾性临床数据分析，我们发现APL患者治疗前后脂质代谢异常。进一步我们发现APL患者在治疗前后均出现TRIB3的高表达，TRIB3通过与PML-RARα相互作用，妨碍脂代谢受体PPARγ与其配基RXR结合，促进PPARγ降解，抑制PPARγ转录活性来介导APL原发和治疗过程后的脂质代谢异常。而联用降脂药PPAR的激动剂（非诺贝特），ATRA/As₂O₃可增强抗白血病效果并缓解病人血脂异常。该研究为临床使用降脂药与ATRA/As₂O₃联用治疗APL提供了重要的理论依据和潜在治疗策略。

淋巴瘤是由病毒、放射线等因素诱发的不同于白血病的血液系统恶性肿瘤。我国淋巴瘤患者大部分为非霍奇金氏淋巴瘤（NHL），随着年龄增加其发病率明显提升。NHL的复发是临床治疗的难点，而肿瘤干细胞的存在是导致淋巴瘤复发的重要原因之一。靶向肿瘤起始细胞或肿瘤干细胞已经成为淋巴瘤治疗的首要目标，而降低关键原癌蛋白的表达则被认为是清除淋巴瘤干细胞的新型策略。本论文第二部分主要集中于假性激酶TRIB3在淋巴瘤发生发展中的作用及机制探究，我们发现TRIB3在淋巴瘤组织中高表达，高表达的TRIB3与淋巴瘤疾病进程密切相关。自发淋巴瘤转基因小鼠中敲除TRIB3能够明显抑制小鼠淋巴瘤的发生发展。机制上，我们发现TRIB3通过与致癌蛋白MYC相互作用，妨碍E3泛素连接酶UBE3B介导的MYC泛素化及降解，维持MYC蛋白的稳定性来维持淋巴瘤细胞的增殖活性和干性，从而促进淋巴瘤的发生发展。本研究首次发现假性激酶TRIB3促进淋巴瘤发生发展的作用，从分子、细胞、动物水平结合PDX模型验证TRIB3促进淋巴瘤发生发展的关键调控机制，同时发现干预措施并提供淋巴瘤的治疗新策略。

本论文围绕假性激酶TRIB3参与APL脂质代谢异常和淋巴瘤发生发展的生物学机制开展了广泛深入的研究。论文第一部分详细阐述TRIB3介导初诊和治疗后APL脂代谢异常的机制，为临床使用降脂药与ATRA/As₂O₃联用治疗APL提供了重要的理论支持。论文第二部分基于TRIB3促进MYC驱动淋巴瘤进展的机制，鉴定出介导MYC泛素化降解的E3泛素连接酶UBE3B，并提出阻断TRIB3/MYC相互作用治疗淋巴瘤的新策略。上述研究为血液肿瘤的治疗提供新策略和新靶点，亦为抗肿瘤多肽药物研发奠定理论基础。

Cancer is a severe disease that seriously threatens public health. Although treatment has made great progress, tumor recurrence, metastasis and drug resistance are still major challenges in clinical treatment. TRIB3 belongs to the pseudoprotein kinases family, which has protein kinase domain but no kinase activity, its biological functions are usually performed by interacting with other critical proteins. TRIB3 participates in protein quality control by acting as stress sensor to connect metabolic stress factors to develop inflammatory diseases and tumors. Our group has explored the roles and mechanisms of TRIB3 in many types of tumors. TRIB3 interacts with various important proto-oncoprotein molecules to change cancer cell biological functions, determine the malignant degree, and even promote cancer occurrence and development, such as leukemia, colorectal cancer, melanoma, liver cancer, lung cancer and breast cancer et al.

Acute promyelocytic leukemia (APL) is a subtype of leukemia and driven by oncogene PML-RARα. TRIB3 is highly expressed in patient samples with APL and inhibits the ubiquitination and degradation of PML-RARα, maintaining APL initiating cells self-renewal ability to promote the disease progression. The current clinical treatment is based on all-trans-retinoic acid (ATRA) combined with arsenic trioxide (As₂O₃). However, there are unsolved problems such as abnormal lipid metabolism and drug resistance. In the first section, we focused on exploring the mechanism of lipid metabolism disorder in patients with APL, found that TRIB3 interacted with PML-RARα and maintained its stability. Both TRIB3 and PML-RARα hindered the binding of PPARγ/RXR, promoted PPARγ degradation and inhibited PPARγ transcription activity, leading to the abnormal lipid metabolism of APL cells. ATRA/As₂O₃ can target and promote the degradation of PML-RARα, and restore PPARγ protein expression in the treatment course. However, drug therapy also increased TRIB3 expression, which destroyed the formation of PPARγ/RXR dimer, inhibited PPARγ activity from mediating lipid metabolism disorder. This study provides necessary theoretical support for the clinical use of lipid regulating drugs and ATRA/As₂O₃ combination.

Lymphoma is a malignant hematologic malignancy, which is different from leukemia. Most of the patients with lymphoma in China are Non-Hodgkin's lymphoma. Lymphoma is often induced by viruses and radiating factors. The incidence rate of lymphoma is obviously increased with age. We found TRIB3 abundance is increased in non-Hodgkin's lymphoma cells, and knocked out TRIB3 can inhibit cell proliferation, stemness and tumor formation. Mechanistically, there is an interaction between TRIB3 and MYC，TRIB3 accelerated the development of lymphoma by regulating the expression of tumor oncoprotein MYC. This study will explain the mechanism of TRIB3 regulating the degradation of MYC and maintaining the stemness of lymphoma initiating cells to promote the occurrence and development of lymphoma. This study identified that the pseudokinase TRIB3 promoted the lymphoma development and detailed biological mechanism in this process.

We have carried out extensive research on the biological mechanism of pseudokinase TRIB3 involved in lipid metabolism abnormalities of APL and lymphoma progression. It elaborates the mechanism of TRIB3-mediated lipid metabolism abnormality of APL at first diagnosis and after treatment. It also provides crucial theoretical support for the clinical use of lipid-lowering drugs combined with ATRA/ As₂O₃ during the treatment of patients with APL. This thesis also reported the mechanism of TRIB3 promoting MYC-driven lymphoma progression and proposed a new strategy to interrupt TRIB3-MYC interaction for lymphoma treatment. The peptide showed anti-tumor effects in vivo and in vitro, which provided new strategies for treatment of lymphoma and a theoretical basis for anti-tumor drug development.