Characterizing MSI2 in leukemia

 描述(申请人提供)：在造血干细胞(HSCs)中小心地维持着一个进化保守的发育程序。遗传改变和表观遗传机制可以改变正常血液发育的平衡，导致血液系统恶性肿瘤。我们最近的研究发现Musashi(MSI2)是一种RNA结合蛋白，控制正常和白血病的自我更新。此外，MSI家族在侵袭性最强的实体瘤中高表达，我们已经证明，MSI2的表达预示着急性髓系白血病(AML)的临床预后更差。我们假设RNA结合蛋白MSI2控制白血病干细胞的自我更新，阐明MSI2在LSCs中的作用机制可能为髓系白血病的治疗提供新的策略。这项建议利用MSI2条件基因敲除和AML患者样本来分析白血病自我更新中对MSI2的需求。此外，我们的全球遗传方法已经揭示了翻译调控如何改变由MLL-AF9癌基因控制的几条表观遗传途径。我们的研究将检测控制LSC功能的MSI2的直接mRNA靶点。此外，我们将根据患者的MSI2表达对患者进行分层，并确定如何使用细胞毒剂、分子靶向和表观遗传疗法来改善AML的治疗结果。

 DESCRIPTION (provided by applicant): An evolutionary conserved developmental program is carefully maintained in hematopoietic stem cells (HSCs). Genetic alterations and epigenetic mechanisms can alter the balance of normal blood development resulting in hematological malignancies. Our recent studies have identified MUSASHI (MSI2), as an RNA binding protein that controls normal and leukemia self-renewal. Moreover, the MSI family is highly expressed in the most aggressive solid tumors and we have demonstrated that MSI2 expression predicts a worse clinical prognosis in acute myeloid leukemia (AML). We hypothesize that the RNA binding proteins MSI2 controls leukemic stem cell self-renewal and elucidating the mechanism of action for MSI2 in LSCs may provide novel therapeutic strategies in myeloid leukemia. This proposal utilizes Msi2 conditional knockouts and patient samples with AML to dissect the requirement for MSI2 in leukemia self-renewal. Furthermore, our global genetic approaches have already uncovered how regulation of translation alters several epigenetic pathways that are controlled by the MLL-AF9 oncogene. Our studies will examine the direct mRNA targets of MSI2 that control LSC function. Additionally, we will stratify patients based on their MSI2 expression and determine how cytotoxic agents, molecular targeted and epigenetic therapies can be used to improve therapeutic outcomes in AML.