ONCOGENESIS AND MYELOID TRANSCRIPTION FACTORS IN AML

了解血细胞正常发育的机制在 了解和开发各种血液疾病的新治疗方法，包括白血病。《长河》 这个项目的范围目标是通过以下方式加深我们对白血病机制的理解 了解不同白血病癌基因对调节正常的转录因子的影响 从干细胞发育成髓系。我们实验室和其他实验室之前的研究已经导致了 转录因子CCAAT增强子结合蛋白α(C/EBPA)和AS的鉴定 对于正常髓系细胞的分化是绝对关键的，并发现C/EBPA异常为 在许多特定类型的急性髓系白血病(AML)中发挥关键作用。过去的研究 授权期已证明AML癌基因，包括PML/RAR和激活的Flt3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，我们建议进一步了解这些 癌基因在细胞分化中影响关键的转录因子功能，以便更有效地发育 并针对这些目标使用药物治疗。这些研究与其他成分具有很强的互动性 这一计划，因为我们将继续与项目1在开发新药组合物方面进行互动 以转录因子为靶点，项目2研究白血病癌基因和 转录因子功能的丧失，以及项目5和核心B在细胞中证实了我们的假设 来源于正在进行临床试验的患者。最后，我们将与新的项目4密切互动，以 研究另一个重要的癌基因对转录因子功能的影响。因此，我们建议 具体目的如下：(1)研究PML/RARα对C/EBPA的影响及其反应 C/EBPβ对全反式维甲酸(ATRA)的作用；(2)建立小鼠模型。 C/EBPA和酪氨酸激酶在AML发生发展中的作用；(3)研究Flt3和Flt3之间的关系。 活化、C/EBPA磷酸化和AML。

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 componentsof 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.