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。

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.