Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation
文献类型：期刊论文
| 作者 | Zhang, Yuan-Liang5; Sun, Jie-Wen5; Xie, Yin-Yin5; Liu, Ping5; Song, Jia-Chun5; Xu, Ai-Ning5; Chen, Zhu5; Chen, Sai-Juan4,5; Sun, Xiao-Jian5; Huang, Qiu-Hua5 |
| 刊名 | CELL RESEARCH
 |
| 出版日期 | 2018 |
| 卷号 | 28期号:4页码:476-490 |
| 关键词 | cadmium wound healing neutrophil chemokine proinflammatory cytokine |
| ISSN号 | 1001-0602 |
| DOI | 10.1038/s41422-018-0015-9 |
| 文献子类 | Article |
| 英文摘要 | 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. |
| 学科主题 | Cell Biology |
| WOS关键词 | HISTONE METHYLTRANSFERASE SETD2 ; RNA-POLYMERASE-II ; MYELODYSPLASTIC SYNDROMES ; DNA-DAMAGE ; BRANCHED EVOLUTION ; METHYLATION ; LEUKEMIA ; MICE ; H3 ; TRANSCRIPTION |
| 语种 | 英语 |
| WOS记录号 | WOS:000432028300010 |
| 出版者 | INST BIOCHEMISTRY & CELL BIOLOGY |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.144/handle/331004/1040]  |
| 专题 | 中国科学院上海生命科学研究院营养科学研究所 |
| 作者单位 | 1.Shanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Key Lab Syst Biomed, Minist Educ, 800 Dongchuan Rd, Shanghai 200240, Peoples R China; 2.Chinese Acad Sci, Inst Hlth Sci, Shanghai Inst Biol Sci, Key Lab Stem Cell Biol, Shanghai 200031, Peoples R China; 3.Shanghai Jiao Tong Univ, Sch Med, Shanghai 200031, Peoples R China; 4.Shanghai Jiao Tong Univ, Natl Res Ctr Translat Med, Sch Med, Shanghai, Peoples R China, 5.Shanghai Jiao Tong Univ, Shanghai Inst Hematol, Rui Jin Hosp, State Key Lab Med Genom,Sch Med, Shanghai 200025, Peoples R China; 6.Shanghai Jiao Tong Univ, Ren Ji Hosp, Cent Lab, Sch Med, Shanghai 200127, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhang, Yuan-Liang,Sun, Jie-Wen,Xie, Yin-Yin,et al. Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation[J]. CELL RESEARCH,2018,28(4):476-490. |
| APA | Zhang, Yuan-Liang.,Sun, Jie-Wen.,Xie, Yin-Yin.,Liu, Ping.,Song, Jia-Chun.,...&,.(2018).Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation.CELL RESEARCH,28(4),476-490. |
| MLA | Zhang, Yuan-Liang,et al."Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation".CELL RESEARCH 28.4(2018):476-490. |
入库方式： OAI收割
来源：上海营养与健康研究所
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