Aberrant signaling in acute myeloid leukemia

急性髓系白血病的异常信号传导

基本信息

批准号：
9335806
负责人：
Alex Kentsis
金额：
$ 45.97万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-22 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335806
关键词：
1-Phosphatidylinositol 3-Kinase Acute Myelocytic Leukemia Adult Apoptosis Apoptotic Biological Biological Markers Cell Survival Cells Child Chromatin Clinical Clinical Trials Combination Drug Therapy Cytotoxic Chemotherapy DNA Damage Development Disease Epigenetic Process FLT3 gene Failure Family Gene Mutation Gene Targeting Genes Genetic Genetic Transcription Genetically Engineered Mouse Genomics Glycogen Synthase Kinase 3 Goals Grant Hematopoietic Human Immunodeficient Mouse Knowledge Link Malignant Neoplasms Mission Molecular Molecular Abnormality Mutation NR4A1 gene Neoadjuvant Therapy Outcome Pathogenesis Pathway interactions Patient Care Patient-Focused Outcomes Patients Pharmacology Phosphorylation Phosphotransferases Public Health Recruitment Activity Refractory Research Research Personnel Research Project Grants Resistance SYK gene Sampling Signal Pathway Signal Transduction Specimen Stem cell transplant Testing Therapeutic Translating Treatment Efficacy Treatment Failure United States National Institutes of Health base cancer cell cell growth chemotherapy clinical care clinically relevant drug metabolism high risk improved innovation insight jun Oncogene leukemia loss of function mutation novel response therapeutic development therapeutic target therapy resistant transcription factor treatment strategy

项目摘要

Project Summary Despite intense efforts, the long-term cure rates of children and adults with acute myeloid leukemia are not satisfactory. Resistance to cytotoxic chemotherapy and apoptosis is the dominant cause of treatment failure. The molecular mechanisms responsible for chemotherapy resistance are poorly understood, hindering the development of therapeutic strategies to induce chemosensitivity. We have found that chemotherapy and apoptosis resistance in high-risk AML requires aberrant phosphorylation of MEF2C, a key transcriptional regulator of leukemia cell growth and survival. The central hypothesis of this proposal is that defining the apoptotic mechanisms dysregulated by aberrant MEF2C signaling will reveal effective therapeutic strategies to overcome treatment resistance. The applicant, who is a New Investigator, will test this hypothesis by investigating the molecular mechanisms of apoptosis resistance in primary human and genetically-engineered mouse leukemias. Aim 1 will elucidate both transcriptional and cellular mechanisms of therapy resistance, with the goal of identifying MEF2C targets that are necessary and sufficient for chemoresistance. Aim 2 will pursue the preliminary evidence that MARK family kinases aberrantly phosphorylate MEF2C and devise rational combination strategies to overcome chemotherapy resistance induced by MEF2C phosphorylation. Successful completion of this project is expected to yield molecular mechanisms of aberrant survival and chemotherapy resistance of high-risk AML, thus providing essential insights into a fundamental biological and clinical problem, which can be rapidly translated into clinical trials for patients with this disease.

项目概要尽管付出了巨大的努力，但儿童和成人急性髓系白血病的长期治愈率仍未达到预期。令人满意。对细胞毒性化疗和细胞凋亡的抵抗是治疗失败的主要原因。对化疗耐药的分子机制知之甚少，这阻碍了化疗耐药性的发展。开发诱导化疗敏感性的治疗策略。我们发现化疗和高危 AML 中的细胞凋亡抵抗需要 MEF2C 的异常磷酸化，MEF2C 是一个关键的转录因子白血病细胞生长和存活的调节剂。该提案的中心假设是定义异常 MEF2C 信号传导失调的细胞凋亡机制将揭示有效的治疗策略克服治疗阻力。作为新研究者的申请人将通过以下方式检验这一假设：研究原代人类和基因工程细胞凋亡抵抗的分子机制小鼠白血病。目标 1 将阐明治疗抵抗的转录和细胞机制，其中确定化学耐药性所必需且充分的 MEF2C 靶标的目标。目标2将追求初步证据表明 MARK 家族激酶异常磷酸化 MEF2C 并设计合理的联合策略克服 MEF2C 磷酸化诱导的化疗耐药性。成功的该项目的完成预计将产生异常生存和化疗的分子机制高风险 AML 的耐药性，从而为基本的生物学和临床问题提供重要的见解，可以快速转化为针对这种疾病患者的临床试验。