Setd2缺失促进Nras-G12D白血病进展的机制研究

近年来，多种恶性血液疾病中发现组蛋白H3K36三甲基转移酶SETD2存在高频失活突变，并可与RAS信号通路存在共突变, 提示SETD2可能具有抑癌作用。然而， 在MLL-AF9小鼠移植模型中，Setd2完全性缺失却显著抑制了白血病的进展。我们先前的工作显示在小鼠中完全性敲除Setd2可损伤造血干细胞自我更新能力，并出现骨髓增生异常综合征样表型，但是稳态下Setd2缺失对白血病进展的影响仍不清楚。为了回答这一问题，通过品系交配我们在Nras-G12D突变模型中敲除了Setd2。不同于MLL-AF9移植模型，Setd2缺失显著加快了Nras-G12D惰性白血病的进展。本项目中，我们将利用此模型探究NrasG12D突变如何克服Setd2缺失所致的干细胞自我更新损伤，进而协同促进白血病的进展，从而帮助我们更好地理解此类白血病的发病机理，为临床治疗提供新的依据。

In the past few years, SETD2, an H3K36me3 specific methyltransferase, was found to be frequently inactivated by mutation in many hematopoietic malignancies. In some cases, co-mutation of SETD2 with RAS signaling pathway associated genes can be detected. These data indicate that SETD2 may act as an important tumor suppressor. However, homozygous deletion of Setd2 significantly inhibited the leukemia progression in MLL-AF9 BM transplant mouse model. Our previous work elucidated that homozygous deletion of Setd2 could impair self-renewal ability of hematopoietic stem cell, resulting in a myelodysplastic syndrome (MDS)-like phenotype (2018,Cell Research). The impact of Setd2 deficiency on leukemia progression under steady-state homeostasis is still unclear. To address this point, we knocked out Setd2 in NrasG12D mouse model by cross-mating. Different from the result generated from MLL-AF9 BM transplant mouse model, our experiment showed that Setd2 deficiency significantly accelerated progression of the inert NrasG12D leukemia. In this project，by using our established Setd2fl/fl/NrasG12D mouse model, we aim to investigate how Nras mutation overcomes the reduction of stem cell self-renewal ability induced by Setd2 deficiency，synergistically promoting the development of leukemia. With this study, we sought to dig out the underlie pathogenesis for this type of leukemia and provide new evidence for clinical therapy.