ONCOGENESIS AND MYELOID TRANSCRIPTION FACTORS IN 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髓系发育的转录因子的影响，进一步了解白血病的机制。来自我们实验室和其他实验室的先前研究已经鉴定了转录因子CCAAT增强子结合蛋白α（C/EBPa），并且其对于正常髓样母细胞的分化是绝对关键的，并且鉴定了C/EBPa的异常在许多特定类型的急性髓性白血病（AML）中起关键作用。在过去的资助期内，研究表明AML癌基因，包括PML/RAR和FLT 3的激活突变可以影响C/EBPa的表达和功能，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 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。这些研究与该项目的其他组成部分高度互动，因为我们将继续与项目1互动，开发靶向转录因子的新药组合，项目2调查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Core B互动，以证实我们在临床试验患者细胞中的假设。最后，我们将与新的项目4密切互动， 研究另一个重要的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/RAR α对C/EBPa的影响，以及C/EBP β对全反式维甲酸（ATRA）的反应;（2）建立AML发生中C/EBPa和酪氨酸激酶联合缺失的小鼠模型;（3）研究FLT 3激活、C/EBPa磷酸化和AML之间的通路。

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.