Dissecting FLT3 signalling in acute myeloid leukaemia

每年约有6000名澳大利亚成年人和儿童被诊断患有白血病、淋巴瘤或相关血液疾病，约占所有癌症的15%。急性髓性白血病（AML）是成人中最常见的白血病形式，其起因是由于持续的异常细胞生长和存活以及正常血细胞形成的阻滞导致未成熟髓性细胞在骨髓和外周血中积聚。仍然有一个主要的研究工作，旨在了解导致AML形成的机制，很明显，多种AML癌基因和肿瘤抑制因子仍有待确定。确定AML中涉及的进一步事件是重要的，因为它将为更特异性和毒性更低的治疗提供途径。这些措施是必要的，因为目前AML的成功率仍然相对较低。至关重要的是，对AML中涉及的途径和事件的理解的研究与治疗药物新方法的快速发展保持同步。这将大大增加未来十年治疗干预的范围。在本申请中，我们研究了一种新的分子途径在AML中的作用。我们的研究已经确定了一个特别感兴趣的基因，我们认为它通常会阻止AML的形成，因此经常被导致AML的细胞变化所关闭。我们认为，沉默该基因在细胞表面受体FLT3突变的AML病例（约30%的AML病例）中特别重要。我们将使用一些分子和细胞生物学方法在小鼠细胞系、正常小鼠细胞和人AML细胞中操纵该基因。更好地了解该基因的作用和涉及FLT3的相关途径可能会为治疗方法产生新的线索。

Each year approximately 6000 Australian adults and children are diagnosed with leukaemia, lymphoma or a related blood disorder, accounting for about 15% of all cancers. Acute Myeloid Leukaemia (AML) is the most common form of leukaemia in adults resulting from an accumulation of immature myeloid cells in the bone marrow and peripheral blood as a result of sustained, abnormal cell growth and survival together with a block in normal blood cell formation. There is still a major research effort aimed at understanding the mechanisms that lead to AML formation and it is clear that multiple AML oncogenes and tumour suppressors remain to be identified. Identification of further events involved in AML is important as it will provide avenues for more specific and less toxic treatments. These are needed because current success rates for AML remain relatively poor. It is critical that research into the understanding of the pathways and events involved in AML keeps pace with the rapid development of new approaches for therapeutic agents. Together this will greatly increase the scope for therapeutic intervention over the next decade. In this application we investigate the role of a new molecular pathway in AML. Our studies have identified a gene of particular interest that we propose normally prevents AML formation and therefore is frequently turned off by the cellular changes that lead to AML. We propose that silencing of this gene is particularly important in those AML cases which have mutations in the cell surface receptor FLT3 (about 30% of AML cases). We will use a number of molecular and cell biology approaches to manipulate this gene in mouse cell lines, normal mouse cells and human AML cells. A better understanding of the role of this gene and the associated pathway involving FLT3 may generate new leads for therapeutic approaches.