Probing the role of the IRE1alpha-XBP1 pathway in normal and malignant hematopoiesis

探讨IRE1α-XBP1通路在正常和恶性造血中的作用

• 批准号: 9371553
• 负责人: Stanley Adoro
• 金额: $ 19.26万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9371553
• 关键词: Ablation; Acute Myelocytic Leukemia; Address; B-Cell Leukemia; Binding Proteins; Biochemical; Blood Cells; Bone Marrow; Cause of Death; Cell Line; Cell Lineage; Cell physiology; Cells; Chemicals; Data; Defect; Dendritic Cells; Development; Developmental Process; Disease; Disease remission; Down-Regulation; Endoplasmic Reticulum; Endoribonucleases; Enzymes; Equilibrium; Eukaryotic Cell; Event; Gene Expression; Gene Targeting; Generations; Genes; Goals; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic stem cells; Homeostasis; Human; Hypoxia; Immunosuppressive Agents; Inositol; Knowledge; Laboratories; Laboratory Research; Leukemic Hematopoietic Stem Cell; LoxP-flanked allele; Malignant - descriptor; Mediating; Membrane; Messenger RNA; Modeling; Molecular; Multiple Myeloma; Mus; Mutation; Myelogenous; Myeloid Leukemia; Myeloproliferative disease; NADPH Oxidase; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Physiological; Population; Process; Proteins; Reactive Oxygen Species; Relapse; Reporter; Reporting; Research; Role; Running; Self-control as a personality trait; Signal Transduction; Stem cells; Testing; Transgenes; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumorigenicity; Up-Regulation; Work; XBP1 gene; beta catenin; biological adaptation to stress; cancer cell; cancer cell differentiation; cancer initiation; cancer stem cell; cancer therapy; career development; cohort; cytokine; experimental study; gain of function; genetic signature; improved; innovation; leukemia; leukemic stem cell; leukemogenesis; mouse model; novel; novel therapeutics; nutrient deprivation; programs; protein folding; proteostasis; research and development; response; self renewing cell; self-renewal; sensor; stressor; transcription factor; transcriptome; triple-negative invasive breast carcinoma; tumor; tumorigenesis; tumorigenic

Project Summary Development of blood cell lineages from hematopoietic stem cells (HSC) is stringently regulated, and defects in this process cause diseases including blood cancers like acute myelogenous leukemia (AML), the most lethal leukemia subtype. Faced with dynamic and potentially oncogenic perturbations in their bone marrow microenvironment, how HSC progenitors balance self-renewal with differentiation and preserve their integrity remains a central question in hematopoiesis. The highly conserved endoplasmic reticulum-membrane kinase- endoribonuclease IRE1α (inositol-requiring enzyme-1), acting through the product of its mRNA substrate X-box binding protein (Xbp)-1, orchestrates an “unfolded protein response” program that facilitates ER protein folding in eukaryotic cells. Beyond this role in cellular proteostasis, I recently discovered that the IRE1α/Xbp1 pathway is a critical cell-intrinsic brake against myeloid leukemogenesis in HSCs. In a mouse model of the Flt3 internal tandem duplication of the juxtamembrane region (Flt3-ITD), the most frequent mutation in AML, HSC- specific loss of IRE1α/Xbp1 caused a lethal AML not seen in WT Flt3-ITD mice. Consistent with these findings, we found that downregulation of an IRE1α/Xbp1 target gene signature was associated with poor overall survival in a cohort of AML patients, revealing the novel possibility that dysregulated IRE1α/Xbp1 signaling importantly contributes to AML pathogenesis. Preliminary transcriptome analysis of IRE1α-deficient HSCs revealed a marked upregulation of Wnt/β-catenin signaling, a key pathway required for the development and function of the “so-called” leukemia stem cells (LSCs), few quiescent and self-renewing cells that initiate, maintain and are implicated in AML relapse but are rarely targeted by current therapies. As IRE1α is a convergence point and sensor for various cellular perturbations (e.g. reactive oxygen species, hypoxia, nutrient deprivation, chemicals, cytokines and metabolites), our findings suggest a novel paradigm in which activation of IRE1α in response to these perturbations restrains the self-renewal potential of HSC progenitors to mitigate leukemogenesis. Using mouse AML models integrating IRE1α activity reporter and inducible Xbp1 transgene that I recently developed, we will address how the IRE1α/Xbp1 pathway is regulated during hematopoiesis (Aim1) and the molecular mechanisms by which this pathway suppresses myeloid leukemogenesis (Aim 2). There is increasing appreciation that because of their important role in AML pathogenesis, eradication of LSCs will be critical to achieve long-term AML remission. As IRE1α/Xbp1 suppresses the Wnt/β-catenin signaling required for LSC function, we will test the hypothesis that targeted activation of the IRE1α/Xbp1 pathway in HSC progenitors will limit LSC development and function (Aim 3), providing an innovative strategy for durable AML therapy. These studies are integral to my long-term commitment to run a strong successful independent research laboratory focused on understanding normal and malignant blood cell development with the ultimate goal of discovering improved therapies for blood cancers.

项目摘要 严格调节造血干细胞（HSC）的血细胞谱系（HSC）的发展，并在 此过程导致包括急性髓性白血病（AML）等血液癌症，最致命的疾病 白血病亚型。面对动态和潜在的骨髓扰动 微环境，HSC祖细胞如何平衡自我更新与差异化并保持其完整性 在造血中仍然是一个核心问题。高度保守的内质网膜激酶 - 内切核核酸酶IRE1α（肌醇重试酶-1），通过其mRNA底物X-box的乘积作用 结合蛋白（XBP）-1，编排了一个“展开的蛋白质反应”程序，该程序有助于ER蛋白质折叠 在真核细胞中。除了在细胞蛋白抑菌中的作用之外，我最近发现IRE1α/XBP1途径 是针对HSC中髓细胞性白血病发生的关键细胞中性制动器。在flt3的鼠标模型中 近膜区域（FLT3-itd）的内部串联重复，AML，HSC-最常见的突变 IRE1α/XBP1的特异性损失在WT FLT3-ITD小鼠中未见致死AML。与这些发现一致 我们发现IRE1α/XBP1靶基因签名的下调与总生存率差有关 在一组AML患者中，揭示了IRE1α/XBP1信号失调的新型可能性 重要的是有助于AML发病机理。 IRE1α缺陷HSC的初步转录组分析 揭示了Wnt/β-catenin信号的明显上调，这是开发和 “所谓的”白血病干细胞（LSC）的功能，几乎没有引发的静态和自我更新细胞 在AML继电器中保持并暗示，但很少受到当前疗法的靶向。因为IRE1α是一个 各种细胞扰动的收敛点和传感器（例如活性氧，缺氧，营养素 剥夺，化学物质，细胞因子和代谢产物），我们的发现提出了一种新型范式，其中激活 对这些扰动的响应，IRE1α限制了HSC祖细胞的自我更新潜力 减轻白血病。使用集成IRE1α活性报告和诱导XBP1的小鼠AML模型 我最近开发的转基因，我们将解决如何调节IRE1α/XBP1途径 造血（AIM1）和该途径抑制髓样的分子机制 白血病发生（AIM 2）。越来越多的赞赏是因为它们在AML中的重要作用 发病机理，消除LSC对于实现长期AML缓解至关重要。作为IRE1α/XBP1 抑制LSC功能所需的Wnt/β-catenin信号传导，我们将测试针对的假设 HSC祖细胞中IRE1α/XBP1途径的激活将限制LSC的发展和功能（AIM 3）， 提供耐用AML治疗的创新策略。这些研究是我的长期不可或缺的 致力于经营强大的成功独立研究实验室，专注于理解正常和 恶性血细胞发育的最终目的是发现改善血液癌的疗法。