Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation
Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation
复制标题
Setd2缺陷损害造血干细胞自我更新并导致恶性转化
DOI：
10.1038/s41422-018-0015-9
复制
发表时间：
2018-04-01
期刊：
影响因子：
44.1
通讯作者：
Huang, Qiu-Hua
中科院分区：
文献类型：
--
作者：
Zhang, Yuan-Liang;Sun, Jie-Wen;Huang, Qiu-Hua
组蛋白H3赖氨酸36甲基转移酶SETD 2在包括白血病在内的各种癌症中经常发生突变。然而，还没有任何功能模型来显示SETD 2在造血中的贡献或SETD 2突变在肿瘤发生中的因果作用。在这项研究中，使用条件性Setd 2基因敲除小鼠模型，我们表明Setd 2缺陷会扭曲造血分化并减少多能祖细胞的数量;尽管Setd 2缺失小鼠中表型造血干细胞（HSC）的数量不变，但功能测定（包括连续骨髓移植）显示HSC的自我更新和竞争力受损。有趣的是，Setd 2缺失的HSC，通过潜伏期，可以获得克服生长劣势的能力，并最终导致骨髓增生异常综合征的造血系统恶性肿瘤特征。Setd 2缺失的造血干/祖细胞（HSPCs）的基因表达谱部分类似于Dnmt 3a/Tet 2双敲除的HSPCs的基因表达谱，显示红系转录因子Klf 1相关通路的激活，其在造血恶性转化中起重要作用。Setd 2缺陷还诱导HSC中的DNA复制应激，如通过激活的E2 F基因调控网络和抑制的核糖核苷酸还原酶亚基Rrm 2b的表达所反映的，这导致增殖和细胞周期异常以及基因组不稳定性，允许协同地促成肿瘤发生的继发突变的积累。因此，我们的研究结果表明，Setd 2是所需的HSC自我更新，并提供证据支持Setd 2缺陷在肿瘤发生的因果关系的作用。其潜在机制将促进我们对癌症表观遗传调控的理解，并提供潜在的新治疗靶点。
The histone H3 lysine 36 methyltransferase SETD2 is frequently mutated in various cancers, including leukemia. However, there has not been any functional model to show the contribution of SETD2 in hematopoiesis or the causal role of SETD2 mutation in tumorigenesis. In this study, using a conditional Setd2 knockout mouse model, we show that Setd2 deficiency skews hematopoietic differentiation and reduces the number of multipotent progenitors; although the number of phenotypic hematopoietic stem cells (HSCs) in Setd2-deleted mice is unchanged, functional assays, including serial BM transplantation, reveal that the self-renewal and competitiveness of HSCs are impaired. Intriguingly, Setd2-deleted HSCs, through a latency period, can acquire abilities to overcome the growth disadvantage and eventually give rise to hematopoietic malignancy characteristic of myelodysplastic syndrome. Gene expression profile of Setd2-deleted hematopoietic stem/progenitor cells (HSPCs) partially resembles that of Dnmt3a/Tet2 double knockout HSPCs, showing activation of the erythroid transcription factor Klf1-related pathway, which plays an important role in hematopoietic malignant transformation. Setd2 deficiency also induces DNA replication stress in HSCs, as reflected by an activated E2F gene regulatory network and repressed expression of the ribonucleotide reductase subunit Rrm2b, which results in proliferation and cell cycle abnormalities and genomic instability, allowing accumulation of secondary mutation(s) that synergistically contributes to tumorigenesis. Thus, our results demonstrate that Setd2 is required for HSC self-renewal, and provide evidence supporting the causal role of Setd2 deficiency in tumorigenesis. The underlying mechanism shall advance our understanding of epigenetic regulation of cancer and provide potential new therapeutic targets.