Targeting IRE-1a/XBP-1 Axis for Control of Chronic GVHD and Leukemia Relapse

摘要 包括白血病和淋巴瘤的血液恶性肿瘤通常用同种异体移植物治疗。 造血干细胞移植（allo-HCT）。然而，慢性移植物抗宿主病（cGVHD） 仍然是移植相关发病率和死亡率的主要原因， 养生法很少有预防策略能成功降低患者cGVHD的发生率， allo-HCT后。一个以前未被探索作为cGVHD治疗的领域涉及未折叠的蛋白质， 答复（普遍定期审议）。三个主调节器控制UPR：PERK、IRE-1α和ATF 6。当IRE-1α成为 激活后，其主要功能是剪接Xbox结合蛋白-1（XBP-1u）mRNA。剪接XBP-1（XBP-1 s） mRNA被翻译成XBP-1蛋白，XBP-1蛋白作为一种有效的核转录因子。免疫 如B细胞增殖和抗体产生的反应需要大量的正确折叠的 proteins. XBP-1蛋白作为一种转录因子，通过上调细胞机械机制来缓解内质网应激 负责蛋白质折叠和降解。因此，XBP-1是效应子功能所必需的， 对ER应激敏感的各种类型的免疫细胞的存活。IRE-1α/XBP-1信号转导轴发挥作用 在其他免疫细胞中，在B细胞和树突细胞（DC）中起主要作用。基于已发表的研究结果 和我们的初步观察，我们将评估IRE-1α/XBP-1信号轴如何影响 通过调节B细胞和DC等，在allo-HCT后发生cGVHD。我们的中央 假设XBP-1在B细胞和DC活化和功能中起重要作用，并且靶向XBP-1 将抑制同种异体反应，从而控制cGVHD，同时保持细胞毒性T细胞的完整性， 淋巴细胞（CTL），从而维持移植物抗白血病（GVL）效应。这一假设将得到检验 在以下两个具体目的中：1）定义XBP-1对造血细胞的贡献， 使用遗传方法在allo-HCT后发生cGVHD; 2）确定 使用药理学方法靶向XBP-1控制cGVHD和白血病复发。当前 这项研究有望进一步了解细胞生物学中UPR是如何调节免疫反应的，揭示UPR的作用。 IRE-1α/XBP-1信号轴在cGVHD和相关血液恶性肿瘤的发展中的作用，以及 为控制allo-HCT后cGVHD和白血病复发提供了新的治疗方法。

Abstract Hematological malignancies that include leukemia and lymphoma are often treated with allogeneic hematopoietic stem cell transplantation (allo-HCT). However, chronic graft-versus-host disease (cGVHD) remains a prominent cause of transplant-related morbidity and mortality despite available immunosuppressive regimens. Few prophylactic strategies have been successful at reducing the incidence of cGVHD in patients after allo-HCT. An area previously unexplored as a treatment for cGVHD involves the unfolded protein response (UPR). Three master regulators control the UPR: PERK, IRE-1α, and ATF6. When IRE-1α becomes activated, its primary function is to splice Xbox binding protein-1 (XBP-1u) mRNA. Spliced XBP-1 (XBP-1s) mRNA is translated into XBP-1 protein which acts as an effective nuclear transcription factor. Immune responses such as B-cell proliferation and antibody production require large amounts of properly folded proteins. As a transcription factor, XBP-1 protein relieves ER stress by up regulating cellular machinery responsible for protein folding and degradation. XBP-1 is therefore required for the effector function and survival of various types of immune cells that are susceptible to ER stress. IRE-1α/XBP-1 signaling axis plays predominate roles in B cells and dendritic cells (DCs) among other immune cells. Built upon published findings and our preliminary observations, we will evaluate how IRE-1α/XBP-1 signaling axis impacts in the development of cGVHD after allo-HCT through regulating B cells and DCs among others. Our Central Hypothesis is that XBP-1 plays an essential role for B-cell and DC activation and function, and targeting XBP-1 will restrain allogeneic responses leading to the control of cGVHD while preserving the integrity of cytotoxic T lymphocytes (CTL) and thus maintaining the graft-versus-leukemia (GVL) effect. This hypothesis will be tested in the following two Specific Aims: 1) Define the contribution of XBP-1 on hematopoietic cells in the development of cGVHD after allo-HCT using a genetic approach; 2) Determine the therapeutic effect of targeting XBP-1 in the control of cGVHD and leukemia relapse using a pharmacological approach. The current study is expected to further understand the cell biology how UPR regulates immune responses, reveal the role for IRE-1α/XBP-1 signaling axis in the development of cGVHD and relatable hematologic malignancies, and provide a novel therapy for controlling cGVHD and leukemia relapse in after allo-HCT.