Cytotoxicity of MLN4924 in Acute Myeloid Leukemia

描述（由申请人提供）：急性髓性白血病（AML）是一种以异常细胞生长和增殖为特征的血癌，常见于成人。据估计，2013年美国将新增14590例AML病例。目前的化疗治疗只能治愈一小部分AML患者；60岁以上患者的5年生存率只有12%。如果白血病继发于现有的血液疾病，即骨髓增生性肿瘤（MPN），则预后更差，患者平均存活时间不到3个月。幸运的是，一种新的化疗药物MLN4924已经进入AML的临床试验，并在不同疾病阶段的患者中显示出抗白血病作用。MLN4924影响恶性细胞中失调的细胞内通路，导致它们经历“程序性细胞死亡”，也称为细胞凋亡。我们的实验室专门研究化疗药物如MLN4924如何诱导细胞凋亡。本申请中提出的研究计划是分子药理学领域更大的研究培训计划的一部分，将使用AML细胞系和临床

DESCRIPTION (provided by applicant): Acute myelogenous leukemia (AML) is a blood cancer found mostly in adults that is characterized by abnormal cell growth and proliferation. It is estimated there will be 14,590 new cases of AML in the U.S. in 2013. Current chemotherapy treatments are able to cure on a fraction of all AML patients; and the five-year survival rate in patients over the age of 60 is a dismal 12%. The prognosis is worse if leukemia occurs secondary to an existing blood disease, known as a Myeloproliferative Neoplasm (MPN), with patients surviving an average of less than 3 months. Fortunately, a new chemotherapy agent, MLN4924, has entered clinical testing in AML and has demonstrated anti-leukemic effects in patients with various stages of disease. MLN4924 affects the intracellular pathways dysregulated in malignant cells to cause them to undergo "programed cell death," also known as apoptosis. Our laboratory specializes in studying how chemotherapeutics such as MLN4924 induce apoptosis. The research plan proposed in this application, which is part of a larger research training plan in the field of molecular pharmacology, will use AML cell lines and clinical samples from newly diagnosed AML patients to investigate the exact mechanism by which MLN4924 induces apoptosis. Specifically, we will be studying how MLN4924 causes changes in the Bcl-2 family of proteins that are known to both positively and negatively regulate apoptosis. We will also study how these proteins change in leukemia cell lines developed from patients with pre-existing MPN. By understanding how these proteins are affected, we may be able to predict which AML patients will respond to MLN4924. Most of the leukemias in MPN patients also have a mutation in a signaling protein called JAK2, which causes the molecule to signal continually and enhance cell growth and survival. Ruxolitinib, a drug designed to inhibit this signaling, has entered clinical trials for treatment of MPN and leukemia arising from MPN. We will also test the combination of MLN4924 and Ruxolitinib in our MPN leukemia cell lines that have this JAK2 mutation. These studies will better define the therapeutic potential of these agents and advance our understanding of how they kill cancer cells on a molecular level. The long-term goal of these studies is to generate knowledge that will help scientists and clinicians develop and implement improved cancer therapies.