Impact of the senescent bone marrow microenvironment in AML biology

项目摘要 急性髓性白血病（AML）是最常见的诊断为成人白血病的疾病， AML大约70岁。尽管在过去的四年中，年轻的AML患者的预后有所改善， 几十年来，老年人的治疗进展甚微。目前，大约90%的成年人 年龄超过55岁的AML患者将因对治疗的抵抗、复发或苛刻治疗的并发症而死亡 例如化疗。AML疾病进展受肿瘤中支持细胞的严重影响 微环境骨髓间充质干细胞（BMSCs）是一种重要的外源性成分 在白血病发展过程中被白血病细胞劫持的正常造血。基于 AML主要是一种老年人疾病，并且在（BM）中有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 并最终确定治疗靶点和消除白血病支持性衰老表型 在BM。虽然表观遗传衰老和衰老是两种不同但平行的衰老机制， 已经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收敛。分子 AML来源的BMSC中年龄相关改变的基础描述不多，如果破译，可能 对老年AML的预防和治疗具有重要意义。此外， 尚未检查AML肿瘤微环境细胞的表观遗传年龄与结果。因此 该建议的具体目的是（1）检查BMSC中的表观遗传、转录和表型差异 来自AML患者，与年龄匹配的对照BSMC相比，通过使用甲基化研究， 测序、质谱细胞计数和生物化学测定（2）通过甲基化分析确定表观遗传年龄 AML患者中肿瘤微环境的不同组分（T细胞、肿瘤细胞和BMSC细胞） 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.在体外和体内加速衰老模型中研究表观遗传衰老和衰老的状态 和复发来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AML患者衰老的定量测量，进一步加强风险分层，以及 这将有助于确定AML-BMSC中与年龄相关的新靶点，并有可能导致新疗法的开发。 在俄亥俄州综合癌症中心的机构支持下，本提案描述了一种培训 计划将我的职业生涯提升为一名具有骨髓老化专业知识的独立调查员 微环境，专注于将发现转化为有影响力的新型疗法， 治疗和早期复发的老年AML患者。在K99阶段，我将得到一位杰出的 顾问和合作者团队为我建立必要的基础，使我能够领导拟议的 研究项目，并作为一个独立的调查员在美国的一个著名的机构前进。

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.