Aberrant signaling in acute myeloid leukemia

项目摘要 尽管付出了巨大努力，但儿童和成人急性髓系白血病的长期治愈率并不高。 令人满意。对细胞毒化疗和细胞凋亡的抵抗是治疗失败的主要原因。 导致化疗耐药的分子机制知之甚少，阻碍了 开发治疗策略以诱导化疗敏感性。我们发现化疗和 高危AML的细胞凋亡抵抗需要MEF2C的异常磷酸化，这是一种关键的转录 白血病细胞生长和存活的调节因子。这项提议的中心假设是，定义 MEF2C信号异常调控的细胞凋亡机制将为临床提供有效的治疗策略 克服治疗耐药性。申请人是一名新的调查员，他将通过以下方式检验这一假设 原代人类和基因工程细胞抗凋亡的分子机制研究 小鼠白血病。目标1将阐明治疗耐药的转录和细胞机制， 目标是确定对化疗耐药是必要和充分的MEF2C靶点。目标2将追求 MARK家族激酶异常磷酸化MEF2C并设计合理的初步证据 克服MEF2C磷酸化诱导的化疗耐药的联合策略。成功 该项目的完成有望获得异常存活和化疗的分子机制。 高危急性髓系白血病的耐药性，从而为基本的生物学和临床问题提供了基本的见解， 它可以迅速转化为对这种疾病患者的临床试验。

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.