Characterizing MSI2 in leukemia

 描述（由申请人提供）：造血干细胞（HSC）中精心维持了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，导致血液恶性肿瘤。我们最近的研究已经确定了MUSASHI（MSI 2），作为一种RNA结合蛋白，控制正常和白血病的自我更新。此外，MSI家族在最具侵袭性的实体瘤中高度表达，并且我们已经证明MSI 2表达预测急性髓性白血病（AML）的更差临床预后。我们假设RNA结合蛋白MSI 2控制白血病干细胞的自我更新，阐明MSI 2在LSC中的作用机制可能为髓性白血病提供新的治疗策略。该提案利用Msi 2条件性敲除和AML患者样本来剖析白血病自我更新中对MSI 2的需求。此外，我们的全球遗传学方法已经揭示了翻译调控如何改变由MLL-AF 9癌基因控制的几种表观遗传途径。我们的研究将检查控制LSC功能的MSI 2的直接mRNA靶点。此外，我们将根据MSI 2表达对患者进行分层，并确定如何使用细胞毒性药物，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.