Bexarotene Induction of Differentiation in AML

贝沙罗汀诱导 AML 分化

• 批准号: 7741035
• 负责人: Patricia Vanessa Sanchez
• 金额: $ 13.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741035
• 关键词: Acute Myelocytic Leukemia; Agonist; Bexarotene; Biological Assay; CEBPE gene; Cell Differentiation process; Cell Line; Cells; Clinical; Comprehension; Data; Differentiation Inducer; Dimerization; Disease; Down-Regulation; FDA approved; Genes; Goals; HL-60 Cells; HL60; Helper-Inducer T-Lymphocyte; Heterodimerization; Heterogeneity; Homodimerization; Hour; In Vitro; Legal patent; Length; Leukemic Cell; Ligands; Mediating; Molecular; Myelogenous; Myeloid Cells; Nuclear Receptors; Pathogenesis; Pathway interactions; Patients; Pennsylvania; Pharmacogenetics; Phosphorylation; Plasmids; Principal Investigator; Process; Protein Isoforms; RNA Interference; RXR; Receptor Activation; Recurrent disease; Regulation; Relapse; Reporting; Retinoic Acid Response Element; Retinoids; Role; Transfection; Tretinoin; Universities; Work; chromatin immunoprecipitation; defined contribution; gene function; in vivo; mortality; mutant; novel; overexpression; programs; promoter; receptor; response; restoration; small hairpin RNA; transcription factor

DESCRIPTION (provided by applicant): Targeted therapy of acute myeloid leukemias (AML) is difficult due to the heterogeneity of the disease. All- trans retinoic acid (ATRA) is currently the only known therapy to work in a subset of AML. Clinicians at the University of Pennsylvania recently demonstrated that the FDA approved retinoid X receptor (RXR) agonist bexarotene stimulated leukemic cell differentiation in a subset of patients with relapsed AML leading to sustained clinical responses. The following proposal aims to characterize the mechanism by which bexarotene induces differentiation in this unique set of patients to further the understanding of how perturbations in RXR stimulated pathways result in acute myeloid leukemias. A pharmacogenetic approach to study the effects of bexarotene on AML cell lines and primary cells will be used. Using AML cell lines and primary cells that have been characterized to be unresponsive and responsive to bexarotene induced differentiation in vitro, we will first define the contribution of RXR activation and dimerization with other nuclear receptors using RNA interference of RXR in responsive AML cells and introduction of the heterodimerization mutant Y402A. Second, we will determine the effects of constitutive up or down- regulation of RXRa on lineage fate and determine the consequence of expression of the non-degradable RXRa S260A mutant on lineage fate determination after stimulation with RXR and RAR agonists. Finally, we will characterize the novel induction of the myeloid transcription factor CEBPe by bexarotene and determine if clinical responses in patients are due to restoration of expression or function of this gene. These studies will provide a more thorough understanding of the regulatory mechanisms of bexarotene-induced differentiation in vitro to further the comprehension of bexarotene responsive AML patients in vivo.

描述（由申请人提供）：由于疾病的异质性，急性髓性白血病（AML）的靶向治疗很困难。全反式维甲酸（ATRA）是目前唯一已知的治疗AML的一个子集。宾夕法尼亚大学的临床医生最近证明，FDA批准的类维生素A X受体（RXR）激动剂贝沙罗汀刺激了一部分复发性AML患者的白血病细胞分化，导致持续的临床反应。以下建议旨在表征贝沙罗汀诱导这组独特患者分化的机制，以进一步了解RXR刺激途径的扰动如何导致急性髓性白血病。将使用药物遗传学方法研究贝沙罗汀对AML细胞系和原代细胞的影响。使用AML细胞系和原代细胞，其特征在于对贝沙罗汀诱导的体外分化无反应和有反应，我们将首先使用应答性AML细胞中RXR的RNA干扰和异源二聚化突变体Y402A的引入来定义RXR活化和与其他核受体的二聚化的贡献。其次，我们将确定RXR α的组成性上调或下调对谱系命运的影响，并确定在用RXR和RAR激动剂刺激后，不可降解的RXR α S260 A突变体的表达对谱系命运确定的结果。最后，我们将描述贝沙罗汀对髓系转录因子CEBPe的新诱导作用，并确定患者的临床反应是否是由于该基因表达或功能的恢复。这些研究将提供对贝沙罗汀体外诱导分化的调控机制的更透彻的理解，以进一步了解体内贝沙罗汀应答的AML患者。