Bexarotene Induction of Differentiation in AML

由于疾病的异质性，急性髓系白血病(AML)的靶向治疗是困难的。所有的- 反式维甲酸(ATRA)是目前已知的唯一对AML子集有效的疗法。医院的临床医生 宾夕法尼亚大学最近证明FDA批准了维甲酸X受体(RXR)激动剂 贝沙罗汀刺激部分复发AML患者的白血病细胞分化，导致 持续的临床反应。以下提案旨在说明以下机制的特点 贝沙罗汀在这组独特的患者中诱导分化，以进一步了解 RXR刺激通路的扰动导致急性髓系白血病。药物遗传学方法 为了研究贝沙罗汀对AML细胞株和原代细胞的影响，将使用贝沙罗汀。使用AML细胞系和 已被描述为对贝沙罗汀诱导的无反应和有反应的原代细胞 在体外分化，我们将首先定义RXR的激活和二聚化与其他 利用RXR干扰反应性AML细胞中的核受体及引入 异二聚化突变体Y402a。第二，我们将确定结构性向上或向下的影响- RXRA对血统命运的调控及决定不可降解基因表达的后果 RXRA S260A突变体在RXR和RAR激动剂刺激后对谱系命运的决定。最后，我们 将表征贝沙罗汀对髓系转录因子CEBPE的新诱导并确定 如果患者的临床反应是由于该基因表达或功能的恢复。这些研究 将提供更深入的了解贝克沙罗汀诱导的调节机制。 体外分化以加深对贝沙罗汀反应性急性髓细胞白血病患者体内的理解。 相关性(请参阅说明)： 尽管在了解AML的分子发病机制方面取得了进展，但对复发疾病的治疗 仍然不足，死亡率为90%。最近FDA批准的药物贝沙罗汀被发现 在部分患者中引起持续的临床反应。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是如何在白血病细胞中出错的。

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.