ONCOGENESIS AND MYELOID TRANSCRIPTION FACTORS IN AML

AML 中的癌发生和骨髓转录因子

• 批准号: 8254467
• 负责人: DANIEL G TENEN
• 金额: $ 47.01万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254467
• 关键词: Acute Myelocytic Leukemia; Affect; Blast Cell; Blood Cells; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Proteins; Cell Differentiation process; Cells; Clinical Trials; Development; FLT3 gene; Family member; Goals; Grant; Hematological Disease; Human; Knowledge; Laboratories; Lead; Mediating; Modeling; Mus; Mutation; Myelogenous; Myeloid Cells; Oncogenes; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phosphorylation; Play; Protein Tyrosine Kinase; Role; Stem Cell Development; Tretinoin; base; functional restoration; kinase inhibitor; leukemia; mouse model; mutant; novel; novel therapeutics; operation; programs; response; retinoic acid receptor alpha; transcription factor; treatment strategy; tumorigenesis

Knowledge of the mechanisms underlying the normal development of blood cells is important in understanding and developing new treatments for various blood diseases, including leukemias. The long range goals of this project are to further our understanding of the mechanisms involved in leukemia by understanding the effect of various leukemia oncogenes on the transcription factors which regulate normal myeloid development from stem cells. Previous studies from our laboratory and others has led to the identification of the transcription factor CCAAT Enhancer Binding Protein alpha (C/EBPa) and as being absolutely critical for differentiation of normal myeloid blasts, and identified abnormalities in C/EBPa as playing critical roles in a number of specific types of Acute Myeloid Leukemia (AML). Studies in the past grant period have demonstrated that AML oncogenes, including PML/RAR and activating mutations of FLT3 can affect the expression and function of C/EBPa, and that drugs that inhibit these oncogenes restore the function of this transcription factor. Over the next 5 years, we propose further our knowledge of how these oncogenes affect critical transcription factor function in cell differentiation in order to more effectively develop and utilize drug therapy aimed at these targets. These studies are highly interactive with other components of this program, in that we will continue our interactions with Project 1 in developing new drug compbinations targeting transcription factors, Project 2 to investigate the co-operation between leukemia oncogenes and loss of transcription factor function, as well as with Project 5 and Core B to confirm our hypotheses in cells derived from patients undergoing clinical trials. Finally, we will interact closely with the new Project 4 to investigate the effect of another important oncogene on transcription factor function. Therefore, we propose the following Specific Aims: (1) To investigate the effects of PML/RAR alpha on C/EBPa , and the response of C/EBP beta to all trans retinoic acid (ATRA); (2) To develop mouse models which combining loss of C/EBPa and tyrosine kinases in development of AML; and (3) To investigate the pathways between FLT3 activation, C/EBPa phosphorylation, and AML.

了解血细胞正常发育的机制对于理解和开发各种血液疾病（包括白血病）的新疗法非常重要。该项目的长期目标是通过了解各种白血病癌基因对调节干细胞正常骨髓发育的转录因子的影响，进一步了解白血病的机制。我们实验室和其他实验室之前的研究已经鉴定出转录因子 CCAAT 增强子结合蛋白 α (C/EBPα) 对于正常髓系母细胞的分化绝对至关重要，并确定 C/EBPα 的异常在许多特定类型的急性髓系白血病 (AML) 中发挥着关键作用。过去资助期的研究表明，AML癌基因，包括PML/RAR和FLT3的激活突变可以影响C/EBPα的表达和功能，而抑制这些癌基因的药物可以恢复该转录因子的功能。在接下来的 5 年里，我们将进一步了解这些 癌基因影响细胞分化中的关键转录因子功能，以便更有效地开发和利用针对这些靶点的药物治疗。这些研究与该计划的其他组成部分高度互动，因为我们将继续与项目 1 合作，开发针对转录因子的新药物组合，与项目 2 合作，研究白血病癌基因和转录因子功能丧失之间的合作，以及与项目 5 和核心 B 合作，在来自接受临床试验的患者细胞中证实我们的假设。最后，我们将与新的Project 4紧密互动， 研究另一种重要癌基因对转录因子功能的影响。因此，我们提出以下具体目标：（1）研究PML/RARα对C/EBPα的影响，以及C/EBPβ对全反式维A酸（ATRA）的反应； (2) 建立在AML发生过程中结合C/EBPα和酪氨酸激酶缺失的小鼠模型； (3)研究FLT3激活、C/EBPα磷酸化和AML之间的途径。