急性髓系白血病（acute myeloid leukemia, AML）是成年人中最为常见的一种急性白血病。随着大批AML病人的全基因组序列被测通，AML的基因组蓝图已初具规模。多数病人都在过度激活的信号通路上携带基因突变，表明其在AML的发生中起着重要作用。其中，发生频率最高的两个突变分别位于FLT3和NRAS/KRAS。为了研究过度激活的Flt3和Ras信号通路如何与其它信号通路协同作用而诱发AML，我们拟建立一个基于CRISPR/Cas9体系的基因敲除文库，在表达过度激活的Flt3-ITD或NrasG12D的基因工程小鼠中进行大规模的基因功能缺失型筛选，以发现能与之协同作用诱导AML的基因突变。我们的研究将构建诱发AML的信号通路网络。这一研究将对揭示AML发生的内在分子机制以及对今后的基因诊断、预后和靶向治疗都有重要意义。

Acute myeloid leukemia (AML) is the most frequent acute leukemia in adults. With whole genome sequencing performed in a large cohort of AML patients, the genomic landscape of AML has been established. Among those patients, more than half have genetic alterations involved in activated signaling pathways, suggesting their important roles in disease development. The most frequent mutation sites locate in FLT3 and NRAS/KRAS. To identify the genetic alterations that synergize with activated Flt3 and Ras signaling pathways to form AML, we propose to conduct CRISPR/Cas9 based loss of function screens in a pooled format using Flt3-ITD and NrasG12D mouse models respectively. Our study will dissect the synergetic mechanisms among different signaling pathways in a systematic manner, which may potentially translate into better diagnosis, prognosis, and targeted therapy in AML.