SETD2 deficiency accelerates MDS-associated leukemogenesis via S100a9 in NHD13 mice and predicts poor prognosis in MDS
SETD2 deficiency accelerates MDS-associated leukemogenesis via S100a9 in NHD13 mice and predicts poor prognosis in MDS
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SETD2 缺陷可通过 NHD13 小鼠中的 S100a9 加速 MDS 相关白血病的发生，并预测 MDS 的不良预后。
DOI：
10.1182/blood.2019001963
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发表时间：
2020-06-18
期刊：
影响因子：
20.3
通讯作者：
Wang, Lan
中科院分区：
文献类型：
--
作者：
Chen, Bing-Yi;Song, Junhong;Wang, Lan
组蛋白H3赖氨酸36位甲基转移酶（H3 lysine 36 methyltransferase，SETD 2）在恶性血液病的发病机制中起重要作用，但其在骨髓增生异常综合征（MDS）中的作用尚不清楚。在这项研究中，低表达的SETD 2与MDS患者的生存期缩短相关，并且这些患者的CD 341骨髓细胞中的SETD 2水平被地西他滨升高。我们在NUP 98-HOXD 13（NHD 13）转基因小鼠中敲除Setd 2，该转基因小鼠表型模仿人MDS，并且发现Setd 2的缺失加速MDS向急性髓性白血病（AML）的转化。Setd 2的缺失增强了NHD 131造血干细胞和祖细胞（HSPC）自我更新的能力，增加了对称的自我更新分裂，减少了分化和细胞死亡。表观遗传修饰药物通过提高H3 K36 me 3水平抑制MDS相关白血病细胞的生长。此外，Setd 2缺陷上调造血干细胞信号传导，下调NHD 131 HSPCs的髓样分化途径。我们的RNA-seq和染色质免疫沉淀-seq分析表明，S100钙结合蛋白S100 a9是Setd 2的靶基因，并且重组S100 a9的加入减弱了NHD 131 HSPC中Setd 2缺陷的影响。相反，S100 a9的下调导致其下游靶点Ikba和Jnk的减少，这些靶点影响HSPCs的自我更新和分化。因此，我们的研究结果表明，SETD 2缺陷预测MDS预后不良，并促进MDS向AML转化，这为MDS相关急性白血病提供了一个潜在的治疗靶点。
SETD2, the histone H3 lysine 36 methyltransferase, previously identified by us, plays an important role in the pathogenesis of hematologic malignancies, but its role in myelodysplastic syndromes (MDSs) has been unclear. In this study, low expression of SETD2 correlated with shortened survival in patients with MDS, and the SETD2 levels in CD341 bone marrow cells of those patients were increased by decitabine. We knocked out Setd2 in NUP98-HOXD13 (NHD13) transgenic mice, which phenocopies human MDS, and found that loss of Setd2 accelerated the transformation of MDS into acute myeloid leukemia (AML). Loss of Setd2 enhanced the ability of NHD131 hematopoietic stem and progenitor cells (HSPCs) to self-renew, with increased symmetric self-renewal division and decreased differentiation and cell death. The growth ofMDS-associatedleukemiacellswasinhibitedthoughincreasingtheH3K36me3levelby using epigenetic modifying drugs. Furthermore, Setd2 deficiency upregulated hematopoietic stem cell signaling and downregulatedmyeloid differentiation pathways in theNHD131 HSPCs. Our RNA-seq and chromatin immunoprecipitation-seq analysis indicated that S100a9, the S100 calcium-binding protein, is a target gene of Setd2 and that the addition of recombinant S100a9 weakens the effect of Setd2 deficiency in theNHD131 HSPCs. In contrast, downregulation of S100a9 leads to decreases of its downstream targets, includingIkbaandJnk, whichinfluence the self-renewalanddifferentiation of HSPCs. Therefore, our resultsdemonstrated that SETD2 deficiency predicts poor prognosis in MDS and promotes the transformation of MDS into AML, which provides a potential therapeutic target for MDS-associated acute leukemia.