Impact of the senescent bone marrow microenvironment in AML biology

项目总结 急性髓系白血病(AML)是成人中最常见的确诊白血病，患者的中位年龄为 急性髓系白血病大约有70年历史。尽管在过去的四年中，患有AML的年轻人的预后有所改善 几十年来，老年人的治疗几乎没有取得什么进展。目前，大约90%的成年人 55岁以上的急性髓细胞白血病将死于治疗抵抗、复发或严苛治疗的并发症 比如化疗。AML疾病进展受到肿瘤中支持细胞的严重影响 微环境。骨髓间充质基质细胞(BMSCs)是一种工具性外在成分 在白血病发展过程中被白血病细胞劫持的正常造血。基座 AML主要是老年人的疾病和BM加速衰老表型的证据 AML的微环境，这项建议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支持白血病的衰老表型 在BM里。虽然表观遗传衰老和衰老是两种截然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聚在一起。分子 AML来源的骨髓间充质干细胞中年龄相关改变的基础描述很差，如果破译，可能会 对老年急性髓系白血病的防治具有重要意义。此外，这种相关性还包括 AML肿瘤微环境中细胞的表观遗传年龄与预后尚未进行检测。因此， 这项建议的具体目的是(1)检查骨髓间充质干细胞的表观遗传学、转录和表型差异。 来自AML患者的，与年龄匹配的对照BSMCs相比，通过甲基化研究的使用， 测序、质谱仪和生化分析(2)通过甲基化分析确定表观遗传年龄 急性髓系白血病患者肿瘤微环境不同成分(T细胞、肿瘤细胞和骨髓间充质干细胞)的比较 样本并与疾病结果相关，最后，(3)利用目标1中开发的研究结果和技术 2在体外和体内加速衰老模型中研究表观遗传衰老和衰老状况 并复发以确定它们是否可以作为治疗靶点。这项工作的完成将有可能 提供老年急性髓细胞白血病患者衰老的量化指标，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，具有开发新疗法的潜力。 在俄亥俄州立综合癌症中心的机构支持下，这项提案描述了一项培训 计划将我的职业生涯提升为一名独立调查员，拥有骨髓老化方面的专业知识 微环境，专注于将发现转化为有效的、针对抗药性的新疗法 急性髓系白血病老年患者的治疗和早期复发。在K99阶段，我将得到一位杰出的 顾问和合作者团队，为我能够领导提议的 在美国一家著名机构担任独立调查员的研究项目和进阶。

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.