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.

项目总结

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.