权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Bexarotene Induction of Differentiation in AML

贝沙罗汀诱导 AML 分化

基本信息

批准号：
8791416
负责人：
Patricia Vanessa Sanchez
金额：
$ 11.13万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791416
关键词：
Bexarotene Induction Differentiation AML

项目摘要

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. RELEVANCE (See instructions): Despite advances in understanding the molecular pathogenesis of AML, therapy for relapsed disease remains inadequate with mortalities of 90%. Recently the FDA approved drug bexarotene was found to induce a sustained clinical response in a subset of patients. This work will be important to identify the mechanism of this response to further the understanding of how these pathways go awry in leukemic cells.

急性髓系白血病（AML）的靶向治疗是困难的，由于疾病的异质性。所有- 反式视黄酸（ATRA）是目前唯一已知的在AML亚组中起作用的疗法。的临床医生宾夕法尼亚大学最近证明，FDA批准的维甲酸X受体（RXR）激动剂贝沙罗汀刺激复发性AML患者亚组的白血病细胞分化，持续的临床反应。以下建议旨在说明这一机制的特点，贝沙罗汀在这组独特的患者中诱导分化， RXR刺激途径的扰动导致急性髓性白血病。药物遗传学方法为了研究贝沙罗汀对AML细胞系和原代细胞的作用，将使用。使用AML细胞系和已被表征为对贝沙罗汀诱导的无应答和应答的原代细胞在体外分化中，我们将首先定义RXR活化和与其他细胞的二聚化的贡献。在应答性AML细胞中使用RXR的RNA干扰的核受体和引入异源二聚化突变体Y402A。第二，我们将确定构成向上或向下的影响- RXR α对谱系命运的调节，并确定非降解的 RXRa S260A突变体对用RXR和RAR激动剂刺激后的谱系命运测定的影响。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，并确定如果患者的临床反应是由于该基因的表达或功能的恢复。这些研究将提供对贝沙罗汀诱导的调节机制的更透彻的理解。本发明的目的在于通过体外分化来进一步理解贝沙罗汀应答性AML患者的体内情况。相关性（参见说明）：尽管在AML的分子发病机制方面取得了进展，但复发性疾病的治疗仍然是一个难题。死亡率高达90%最近FDA批准的药物贝沙罗汀被发现在一部分患者中诱导持续的临床反应。这项工作对于确定这种反应的机制，以进一步了解这些途径如何在白血病细胞出错。