Impact of the senescent bone marrow microenvironment in AML biology

衰老骨髓微环境对 AML 生物学的影响

• 批准号: 10553363
• 负责人: Amina Abdul-Aziz
• 金额: $ 6.82万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553363
• 关键词: Acute Myelocytic Leukemia; Adult; Affect; Age; Aging; Biochemical; Biological Assay; Biology; Bone Marrow; Cell Aging; Cells; Cessation of life; Chemoresistance; Chronic; Comprehensive Cancer Center; Cytometry; Deceleration; Development; Diagnosis; Disease; Disease Outcome; Disease Progression; Disease Resistance; Disease remission; Disease-Free Survival; Early treatment; Elderly; Elderly Acute Myeloblastic Leukemia; Epigenetic Process; Foundations; Genes; Genetic Transcription; Genomics; Growth; Hematopoiesis; In Vitro; Inflammatory; Institution; Lead; Leukemic Cell; Malignant Neoplasms; Measures; Mentors; Metabolic; Methylation; Modeling; Molecular; Ohio; Oncogenic; Outcome; Patients; Phase; Phenotype; Prevention; Process; Prognosis; Relapse; Research Personnel; Research Project Grants; Role; Sampling; Supporting Cell; T-Lymphocyte; Techniques; Training; Transcriptional Regulation; Translating; United States; Work; acute myeloid leukemia cell; adult leukemia; age related; base; career; cell age; chemotherapy; disease natural history; epigenetic regulation; improved; in vivo Model; insight; leukemia; mesenchymal stromal cell; mortality; neoplastic cell; new therapeutic target; novel; novel therapeutics; risk stratification; senescence; therapeutic target; therapy resistant; tumor; tumor microenvironment; young adult

PROJECT SUMMARY Acute myeloid leukemia (AML) is the most common diagnosed adult leukemia, the median age of patients with AML is about 70 years. Although the prognosis for younger adults with AML has improved during the last four decades, there has been little progress in the treatment of older adults. Currently, approximately 90% of adults with AML over the age of 55 will die due to resistance to therapy, relapse, or complications from harsh treatments such as chemotherapy. AML disease progression is heavily influenced by supportive cells in the tumor microenvironment. Bone marrow mesenchymal stromal cells (BMSCs) are an instrumental extrinsic component to normal hematopoiesis which are hijacked by leukemic cells in the process of leukemia development. Based on AML being mainly a disease of older adults and evidence of an accelerated aging phenotype in the (BM) microenvironment of AML, this proposal aims to investigate the role of aging and senescence in AML disease progression and to ultimately identify therapeutic targets and eliminate the leukemia-supportive aging phenotype in the BM. Although epigenetic aging and senescence are two distinct but parallel mechanisms of aging, they have been shown to converge where certain triggers of senescence can affect epigenetic age. The molecular basis for age-related alterations in AML-derived BMSCs are poorly described and if deciphered, could have significant implication on both the prevention and treatment of elderly AML. Moreover, the correlation of epigenetic age in cells of the AML tumor microenvironment with outcome has not been examined. Thus, the specific aims of this proposal are to (1) examine epigenetic, transcriptional and phenotypic differences in BMSCs derived from AML patients, compared to age matched control BSMCs, enabled by the use of methylation studies, sequencing, mass cytometry and biochemical assays (2) determine the epigenetic age via methylation analysis of different components of the tumor microenvironment (T-cells, tumor cells and BMSC cells) in AML patient samples and correlate with disease outcome and finally, (3) utilize findings and techniques developed in aim 1 and 2 to study the status of epigenetic aging and senescence in in vitro and in vivo models of accelerated aging and relapse to determine if they can be therapeutically targeted. The completion of this work will potentially provide a quantitative measure of senescence in elderly AML patients, further enhance risk stratification, and will help identify novel age-related targets in AML-BMSC with potential to lead to development of new therapies. With institutional support of the Ohio State Comprehensive Cancer Center, this proposal describes a training plan to advance my career to an independent investigator with expertise in aging in the bone marrow microenvironment, focused on translating discoveries to impactful, novel therapeutics that target resistance to therapy and early relapse in older adults with AML. During the K99 phase, I will be supported by an outstanding team of advisors and collaborators to build the necessary foundation for me to be able to lead the proposed research project and advance as an independent investigator at a distinguished institution in the United States.

项目概要 急性髓系白血病 (AML) 是最常见的成人白血病，患者的中位年龄 AML大约有70年的历史。尽管患有 AML 的年轻成人的预后在过去四年中有所改善 几十年来，老年人的治疗几乎没有取得任何进展。目前，大约 90% 的成年人 55岁以上的AML患者将因治疗耐药、复发或严酷治疗的并发症而死亡 比如化疗。 AML疾病进展很大程度上受到肿瘤支持细胞的影响 微环境。骨髓间充质基质细胞 (BMSC) 是一种重要的外在成分 正常造血功能在白血病发展过程中被白血病细胞劫持。基于 AML 主要是一种老年人疾病以及 (BM) 中加速衰老表型的证据 AML的微环境，该提案旨在研究衰老和衰老在AML疾病中的作用 进展并最终确定治疗靶点并消除白血病支持的衰老表型 在BM中。尽管表观遗传衰老和衰老是两种不同但平行的衰老机制，但它们 已被证明在某些衰老触发因素可以影响表观遗传年龄的地方会趋同。分子 AML 衍生的 BMSC 中与年龄相关的改变的基础尚不清楚，如果破译，可能会 对老年AML的预防和治疗具有重要意义。此外，相关性为 尚未检查 AML 肿瘤微环境细胞的表观遗传年龄及其结果。因此， 该提案的具体目标是 (1) 检查 BMSC 的表观遗传、转录和表型差异 与年龄匹配的对照 BSMC 相比，源自 AML 患者，通过使用甲基化研究实现， 测序、质谱流式细胞仪和生化分析 (2) 通过甲基化分析确定表观遗传年龄 AML患者肿瘤微环境不同成分（T细胞、肿瘤细胞和BMSC细胞）的变化 样本并与疾病结果相关联，最后，(3) 利用目标 1 中开发的发现和技术 2 在加速衰老的体外和体内模型中研究表观遗传衰老和衰老的状态 并复发以确定它们是否可以作为治疗目标。这项工作的完成可能会 提供老年 AML 患者衰老的定量测量，进一步加强风险分层，以及 将有助于确定 AML-BMSC 中与年龄相关的新靶点，并有可能开发新疗法。 在俄亥俄州立综合癌症中心的机构支持下，该提案描述了一项培训 计划将我的职业生涯提升为一名拥有骨髓衰老方面专业知识的独立研究者 微环境，专注于将发现转化为针对耐药性的有影响力的新型疗法 老年人 AML 的治疗和早期复发。在K99阶段，我将得到优秀的支持 顾问和合作者团队为我能够领导拟议的项目奠定了必要的基础 研究项目并作为独立研究员在美国著名机构取得进展。

项目成果

Mass Cytometry as a Tool for Investigating Senescence in Multiple Model Systems.

• DOI: 10.3390/cells12162045
• 发表时间: 2023-08-11
• 期刊: CELLS
• 影响因子: 6
• 作者: Abdul-Aziz, Amina;Devine, Raymond D.;Lyberger, Justin M.;Chang, Hsiaochi;Kovacs, Amy;Lerma, James R.;Rogers, Andrew M.;Byrd, John C.;Hertlein, Erin;Behbehani, Gregory K.
• 通讯作者: Behbehani, Gregory K.