Targeting ER stress response in B-cell chronic lymphocytic leukemia

靶向 B 细胞慢性淋巴细胞白血病的 ER 应激反应

• 批准号: 10330198
• 负责人: Chih-Chi Andrew Hu
• 金额: $ 41.58万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330198
• 关键词: Affect; Aftercare; Apoptosis; B Cell Proliferation; B cell differentiation; B lymphoid malignancy; B-Cell Antigen Receptor; B-Lymphocytes; Bacterial Polysaccharides; Binding; Cancer Center; Chronic Lymphocytic Leukemia; Clinical; DNA; Data; Drops; Emu species; Endoplasmic Reticulum; Event; Exposure to; FDA approved; Genes; Genetic; Goals; Growth; Human; Immune system; Immunomodulators; In Vitro; Knock-in; Knock-out; Knockout Mice; Ligands; Lipoproteins; Malignant - descriptor; Malignant Neoplasms; Mature B-Lymphocyte; Messenger RNA; Mus; Natural Immunity; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Phosphotransferases; Play; Receptor Cell; Receptor Signaling; Reporting; Role; Sampling; Serine; Signal Pathway; Signal Transduction; System; Testing; Toll-like receptors; Toxic effect; Viral; adult leukemia; base; biological adaptation to stress; cancer cell; chronic lymphocytic leukemia cell; combat; endoplasmic reticulum stress; in vivo; inhibitor/antagonist; kinase inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; mouse model; novel; prevent; receptor; response; small molecule inhibitor; tool

Project Summary/Abstract Chronic lymphocytic leukemia (CLL) is an incurable B cell malignancy that represents 30% of all adult leukemia. Although the initiating events are unclear, exposure to factors such as bacterial polysaccharides, lipoproteins, and DNA has been proposed to drive proliferation in CLL, via binding to the B cell receptor (BCR). These factors also serve as ligands for Toll-like receptors (TLRs), a class of receptors critical for innate immunity and that play multiple roles in B cell differentiation and activation. However, exactly how TLR ligands are involved in CLL is unclear, as some studies observe apoptosis after treatment of CLL cells with TLR ligands and other studies observe proliferation. Understanding which ligands have which effects is particularly crucial at present, as TLR ligands are proposed as immunomodulatory agents to coach our immune system to combat CLL. As a clinical case in point, ibrutinib is used to inhibit the BCR signaling that drives proliferation of CLL; but approximately 60% of CLL patients treated with ibrutinib at the Moffitt Cancer Center dropped out of the therapy due to toxicity. In addition, CLL undergoes Richter's transformation into fast-growing diffuse large B cell lymphoma in increasing numbers of patients receiving ibrutinib therapy. Hence, halting B cell proliferation in CLL remains a challenge. Our group used our in-depth understanding of the endoplasmic reticulum (ER) signaling to consider this problem from a different angle, finding that for CLL cells to survive they require activation of the ER stress response. We also found that the IRE-1/XBP-1 pathway of the ER stress response is activated by TLR ligands, to promote proliferation of CLL cells in vitro. These results led us to hypothesize that in CLL cells, specific TLR ligands activate the IRE-1/XBP-1 pathway through TLR and BCR signaling, to promote malignant progression of CLL. We have generated a novel mouse model in which the XBP-1 gene is knocked out specifically in B cells in Eµ-TCL1 (CLL) mice, and showed that BCR signaling is downregulated in XBP-1-deficient Eµ-TCL1 B cells. In addition, we have developed a specific and potent inhibitor of the IRE- 1/XBP-1 pathway, B-I09, which induces apoptosis of CLL in vivo and does not exhibit overt toxicity in mice. Treatment with B-I09 also reduced BCR signaling in Eµ-TCL1 B cells. Using these novel tools, we will determine exactly which TLR ligands promote malignant progression of CLL in vivo via activation of the IRE- 1/XBP-1 pathway and BCR signaling, and whether targeting the IRE-1/XBP-1 pathway can thwart the two- pronged effect of TLR ligands. Based on our new data, we also propose to test whether CLL cells lacking XBP- 1s may activate regulated IRE-1-dependent decay (RIDD) to counter apoptosis. These goals are summarized in the following specific aims. Aim 1: Establish that TLR ligand-induced activation of the ER stress response supports malignant progression of CLL in vivo, and proliferation and survival of human CLL cells. Aim 2: Investigate whether targeting XBP-1 decelerates TLR ligand-induced progression of CLL by suppressing BCR signaling. Aim 3: Investigate how RIDD contributes to the progression of CLL in XBP-1KO/Eµ-TCL1 mice.

项目摘要/摘要 慢性淋巴细胞性白血病（CLL）是一种无法治愈的B细胞恶性肿瘤，占所有成年人的30％ 白血病。尽管发射事件尚不清楚，但暴露于细菌多糖等因素， 脂蛋白和DNA已被提议通过与B细胞受体（BCR）结合来驱动CLL的增殖。 这些因素还用作Toll样受体（TLR）的配体，这是一种对先天性至关重要的受体 免疫力，该免疫力在B细胞分化和激活中起多种作用。但是，确切的TLR配体 参与CLL尚不清楚，因为一些研究观察到用TLR处理CLL细胞后的凋亡 配体和其他研究观察到增殖。了解哪些配体有哪些效果特别是 目前，至关重要的是，由于TLR配体被提议为免疫调节剂，以指导我们的免疫系统 战斗Cll。作为一个临床的例子，ibrutinib用于抑制驱动增殖的BCR信号传导 cll;但是大约60％的CLL患者在莫菲特癌症中心接受了ibrutinib治疗 由于毒性而引起的治疗。此外，CLL经历了Richter的转化为快速增长的大型B 细胞淋巴瘤在接受依鲁替尼治疗的患者人数增加中。因此，停止B细胞增殖 在CLL中仍然是一个挑战。我们的小组使用了我们对内质网（ER）的深入了解 信号从不同的角度考虑这个问题，发现Cll细胞生存需要 ER应力反应的激活。我们还发现ER应力响应的IRE-1/XBP-1途径 被TLR配体激活，以促进体外CLL细胞的增殖。这些结果导致我们假设 在CLL细胞中，特定的TLR配体通过TLR和BCR信号激活IRE-1/XBP-1途径， 促进CLL的恶性进展。我们已经生成了一个新型的鼠标模型，其中XBP-1基因为 在Eµ-TCL1（CLL）小鼠的B细胞中专门敲出，并表明BCR信号在 XBP-1缺陷Eµ-TCL1 B细胞。此外，我们已经开发了一个特异性且潜在的抑制剂 1/XBP-1途径B-I09，诱导Cll在体内凋亡，并且在小鼠中不存在明显的毒性。 用B-I09处理还降低了Eµ-TCL1 B细胞中的BCR信号传导。使用这些新颖的工具，我们将 确切确定哪种TLR配体通过激活IRE-促进CLL的恶性进展 1/XBP-1途径和BCR信号传导，以及针对IRE-1/XBP-1途径是否可以阻止两种 TLR配体的抬起作用。基于我们的新数据，我们还建议测试是否缺乏XBP-的CLL细胞 1s可能会激活受调节的IRE-1依赖性衰减（RIDD）来对抗凋亡。这些目标总结 在以下特定目标中。目标1：确定TLR配体诱导的ER应力反应激活 支持CLL体内CLL的恶性进展，以及人类CLL细胞的增殖和存活。目标2： 研究靶向XBP-1是否通过抑制BCR来减速TLR配体诱导的CLL进展 信号。 AIM 3：研究RIDD如何促进XBP-1KO/Eµ-TCL1小鼠中CLL的进展。