Sirt2 在MLL-r急性粒细胞白血病发生发展和耐药中的作用

Acute myeloid leukemia (AML) with MLL-rearrangement (MLL-r) is a common type of AML with miserable prognosis. Development of effective medications for such AML is urgent. We found that although Sirt2, a NAD+ deacetylase, is highly expressed in MLL-r AML cells, Sirt2 activity in vivo is repressed by bone marrow niche signaling through induced phosphorylation of Sirt2S368. As a consequence， NF-kB-K310 and Stat3-K685 are hyperacetylated. Acetylated NF-kB and Stat3 have high transcriptional activity, promoting AML development, disease progression and drug-resistance. Genetic knockout study demonstrated that Sirt2 inactivation promotes AML development and induces drug resistance in MLL-r AML. This suggested that Sirt2 is a repressor for MLL-r AML. We propose that activation of Sirt2 by inactivation of the niche signaling or repression of NF-kB and Stat3 acetylation is a useful treatment strategy for MLL-r AML when combined with standard chemotherapy. We want to test our hypothesis by introducing Sirt2-S368A, Sirt2-S368E, NF-kB-K310R and/or Stat3-K685R mutations into Sirt2 deficient AML cells using viral infection or Crispr-mediated editing techniques. We will then transplant such genetic modified AML cells into recipient mice in order to determine whether inhibition of Sirt2 phosphorylation or repressing NF-kB/Stat3 acetylation can suppress MLL-r AML development and sensitize MLL-r AML cells to chemotherapy. The expected result of this study will provide us useful information for better understand the bone marrow niche signaling in AML pathogenesis and allow us to develop novel treatment strategy for MLL-r AML.

MLL-r急性粒细胞白血病(AML)为常见的难治性AML。我们发现:1.Sirt2在MLL-r AML细胞高表达，其功能在体内被组织微环境中的信号通过诱导激酶介导的磷酸化而抑制，与其相伴随的是NF-κB和Stat3的乙酰化增加; 2.NF-κB和Stat3的乙酰化受到Sirt2的调节，Sirt2-/- AML细胞的致病能力和对化疗的耐受能力均高于Sirt2野生型AML细胞。 提示：在MLL-r AML 细胞中，Sirt2通过去乙酰化NF-κB和Stat3而抑制AML的发生发展和促进AML细胞对化疗的敏感性。骨髓微环境中信号通过刺激Sirt2S368位点的磷酸化而抑制Sirt2的活性、促进AML细胞的致病能力。推测通过干预Sirt2磷酸化而促进Sirt2的活性可能为治疗MLL-r AML的有效策略。本研究将揭示骨髓微环境Sirt2-NF-κB/Stat3信号调节AML发展和化疗敏感性的作用。

MLL-r急性粒细胞白血病(AML)为常见的难治性AML。本课题主要研究了：1） 研究 Sirt2 S368 位点的磷酸化在 MLL-r AML 发生发展和耐药中的作用，明确是否可以通过抑制 Sirt2 S368 的磷酸化而促进AML细胞中 Sirt2 的活性、抑制AML的发生发展和促进AML细胞对化疗药物的敏感性。 2） 研究 Sirt2是不是通过对NF-κB和Stat3 的去乙酰化而抑制AML的发生发展 和调节AML细胞的耐药性，揭示Sirt2 抑制AML发生发展及促进AML细胞对化疗耐受的机制。研究发现，Sirt2通过去乙酰化NF-κB和Stat3而抑制AML的发生发展和促进AML细胞对化疗的敏感性。同时，通过突变Sirt2S368位点，抑制磷酸化后，Sirt2活性提高，从而降低了AML细胞的致病能力。另外，我们还发现，Sirt2的去乙酰化酶活性能保护c-Myc原癌蛋白免受蛋白酶体和calpain的降解。以上结果，为AML白血病的治疗提供了新的思考角度。