Cooperating genes in inv(16) acute myeloid leukemia

inv(16)急性髓系白血病的协同基因

• 批准号: 6787760
• 负责人: LUCIO H. CASTILLA
• 金额: $ 31.84万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6787760
• 关键词: Cooperating; genes; inv; 16; acute

DESCRIPTION (provided by applicant): Acute myeloid leukemias (AML) arise from the uncontrolled clonal expansion of hematopoietic progenitor cells. Different subtypes of AML are associated with specific chromosomal translocations. For example, the subtype M4Eo is associated with the chromosome 16 break-and-join inversion of the genes that code for the fusion gene CBFb-MYH11. Within subtypes, additional mutations have also been found in other genes including Ras, p53, and NFl. These mutations could play a role in CBFB-MYH11 mediated AML .We generated the Cbfb-MYH11 knock-in mouse, mimicking the presence of CBFb-MYH11 in human AML-M4Eo. We have shown that Cbfb-MYH11 plays a role in leukemogenesis by blocking hematopoietic differentiation. We hypothesize that AML is the result of a process that involves two-events: 1. The creation of a fusion gene that alters hematopoietic stem cell differentiation and 2. the introduction of one or more other mutations that are associated with apoptosis and/or proliferation. To test these hypotheses we will identify genes that synergize with Cbfb-MYH11 to develop AML. We will first combine retroviral insertional mutagenesis in our knock in mice with inverse PCR to identify genes altered in AML (Aim 1). We will then use retroviral transduction of identified genes and transplantation experiments to test for a transforming role of these genes. As an alternative approach to test our hypotheses, we will use genetic crosses and retroviral transduction experiments to evaluate the functional interactions between Ras associated genes and Cbfb-MYH11 in AML development (Aim 2). Our long-term goals are to understand the genetic mechanisms that determine AML, and to provide targets for the design of improved therapies.

描述（由申请人提供）：急性髓性白血病（AML）由造血祖细胞的不受控制的克隆扩增引起。AML的不同亚型与特定的染色体易位相关。例如，亚型M4 Eo与编码融合基因CBFb-MYH 11的基因的染色体16断裂-连接倒位相关。在亚型内，在其他基因中也发现了另外的突变，包括Ras、p53和NF 1。这些突变可能在CBFB-MYH 11介导的AML中发挥作用。我们产生了Cbfb-MYH 11敲入小鼠，模拟人AML-M4 Eo中CBFb-MYH 11的存在。我们已经表明，Cbfb-MYH 11通过阻断造血分化在白血病发生中发挥作用。我们假设AML是一个涉及两个事件的过程的结果：1。创建一个融合基因，改变造血干细胞分化和2。引入一种或多种与凋亡和/或增殖相关的其它突变。为了验证这些假设，我们将鉴定与Cbfb-MYH 11协同作用以发展AML的基因。我们将首先将联合收割机逆转录病毒插入突变在我们的敲入小鼠中与反向PCR相结合，以鉴定AML中改变的基因（目的1）。然后，我们将使用已鉴定基因的逆转录病毒转导和移植实验来测试这些基因的转化作用。作为检验我们假设的替代方法，我们将使用遗传杂交和逆转录病毒转导实验来评估Ras相关基因和Cbfb-MYH 11在AML发展中的功能相互作用（目的2）。 我们的长期目标是了解决定AML的遗传机制，并为改进疗法的设计提供目标。