Mechanistic and functional dissection of myeloid blood cancers

髓系血癌的机制和功能剖析

• 批准号: 10228698
• 负责人: Shannon Elisabeth Elf
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228698
• 关键词: Acute Myelocytic Leukemia; Award; Binding; Calcium; Cell Survival; Cells; Clinical; Dependence; Development; Dimerization; Disease; Dissection; Endoplasmic Reticulum; Genes; Genetic; Goals; Hematopoietic; Hematopoietic Neoplasms; Homeostasis; Isocitrate Dehydrogenase; MPL gene; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Molecular; Molecular Chaperones; Mutate; Mutation; Myelogenous; Myeloid Cells; Myeloproliferative disease; Oncogenes; Oncogenic; Oxidation-Reduction; Pathogenicity; Pathway interactions; Phase; Play; Proteins; Publishing; Research; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic; Thrombopoietin; Translating; Work; acute myeloid leukemia cell; calreticulin; cancer cell; cell transformation; endoplasmic reticulum stress; exome sequencing; improved; insight; leukemogenesis; misfolded protein; mutant; non-oncogenic; novel therapeutics; response; restoration; targeted treatment; therapeutic target; treatment strategy

Abstract Although the genes that drive the development of myeloid blood cancers have largely been defined, there are currently very few effective targeted therapies for these diseases. This illuminates the need to exploit the molecular understanding that has been gained in the last decade through cancer exome sequencing to identify unique therapeutic vulnerabilities in myeloid malignancies. We recently identified the mechanism by which mutant calreticulin (CALR) is oncogenic in myeloproliferative neoplasms (MPN), a subtype of myeloid blood cancers. This work revealed the following key findings: (i) The thrombopoietin receptor, MPL is absolutely required for mutant CALR-mediated hematopoietic transformation, (ii) mutant CALR activates JAK/STAT signaling downstream of MPL, and (iii) the C-terminus of mutant CALR is required for its oncogenic activity, through facilitating a physical interaction between mutant CALR and MPL. However, the mechanism by which the binding between mutant CALR and MPL activates pathogenic MPL signaling remains unknown. I will seek to answer this in Specific Aim 1 of this proposal. Although such dissection of the molecular mechanisms underlying oncogenic proteins in myeloid malignancies is a crucial step in developing rational approaches to therapy, it is perhaps even more critical to identify unique, non-oncogenic molecular vulnerabilities in cells transformed by these oncogenes. In recent years, the unfolded protein response (UPR) has emerged as a major regulator of cancer cell survival. The UPR orchestrates the restoration of ER function to help cancer cells adapt to microenvironmental changes, including those that disrupt redox, calcium, and metabolic homeostasis. As an endoplasmic reticulum (ER) chaperone, CALR is a critical UPR effector. However, the role of the UPR in mutant CALR-driven MPN has yet to be studied. In Specific Aim 2 of this proposal, I will determine whether mutant CALR-transformed cells are dependent on the UPR for survival, and whether this pathway can be targeted for therapeutic gain in MPN. In the R00 phase (Specific Aim 3) of this proposal, I will employ the insight gained through the study of the UPR in MPN to investigate whether this pathway is important in more aggressive myeloid blood cancers such as acute myeloid leukemia (AML). Although the UPR has been demonstrated to play a role in myeloid leukemogenesis, it has only been interrogated in a limited number of genetic subtypes of AML. Despite the fact that many AML mutations are associated with altered metabolic homeostasis and likely engage the UPR as a result, the role of this pathway in the context of such mutations has yet to be explored. In an entirely new line of study, I will interrogate the UPR specifically in genetic subsets of AML where cellular metabolism is dysregulated, and determine whether targeting this pathway represents a new therapeutic avenue in the treatment of AML.

摘要 尽管推动髓系血液癌发展的基因在很大程度上已经被定义，但有 目前，针对这些疾病的有效靶向治疗很少。这说明有必要利用 过去十年通过癌症外显子组测序来识别 髓系恶性肿瘤独特的治疗脆弱性。我们最近确定了 突变的钙网蛋白(CALR)在骨髓增生性肿瘤(MPN)中是致癌的，MPN是髓系血液的一种亚型 癌症。这项工作揭示了以下主要发现：(I)血小板生成素受体，MPL绝对是 突变的CALR介导的造血转化所必需的：(Ii)突变的CALR激活JAK/STAT MPL下游的信号，以及(Iii)突变体CALR的C末端是其致癌活性所必需的， 通过促进突变体CALR和MPL之间的物理相互作用。然而，通过这种机制 突变的CALR和MPL之间的结合激活致病的MPL信号仍不清楚。我会去寻找 在本提案的具体目标1中回答这一问题。尽管这种对分子机制的剖析 髓系恶性肿瘤的潜在致癌蛋白是开发合理的治疗方法的关键一步 在治疗方面，识别细胞中独特的、非致癌的分子脆弱性可能更加关键 被这些致癌基因转化了。近年来，未折叠蛋白反应(UPR)已经成为一种 癌细胞存活的主要调节因子。UPR协调ER功能的恢复以帮助癌细胞 适应微环境的变化，包括那些破坏氧化还原、钙和代谢动态平衡的变化。 作为内质网(ER)的伴侣，CALR是一个重要的UPR效应因子。然而，普遍定期审议在以下方面的作用 突变的CALR驱动的MPN还有待研究。在本提案的具体目标2中，我将确定是否 突变的CALR转化的细胞依赖于UPR生存，以及这一途径是否可以 以MPN的治疗收益为目标。在本提案的R00阶段(具体目标3)，我将采用 通过对MPN中UPR的研究获得的洞察力，以调查这一途径是否在更多的 侵袭性髓系血癌，如急性髓系白血病(AML)。尽管普遍定期审议一直是 它被证明在髓系白血病的发生中起作用，但仅在有限数量的 AML的遗传亚型。尽管许多AML突变与代谢改变有关 动态平衡并可能因此参与UPR，这一途径在这种突变的背景下的作用 还有待探索。在一种全新的研究中，我将具体询问遗传亚群中的普遍定期审议 细胞代谢紊乱的AML，并确定靶向这一途径是否代表 治疗急性髓系白血病的新途径。