Abstract
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.
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Acknowledgments
We thank Prof. Bo Zhou from Shanghai Institute of Biochemistry and Cell Biology for his constructive comments. We thank Shu-Min Xiong, Min Zhang, Jing Xie and other colleagues for their help and support. This work was supported by National Natural Science Foundation of China (81500080, 81670149); National Key Basic Research Project (973, 2013CB966801); 1000 Talents Program for Young Scholars; Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20152506); and Samuel Waxman Cancer Research Foundation.
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Z.Y.L., H.Q.H., S.X.J., C.S.J., and C.Z. designed the experiments and wrote the manuscript. Z.Y.L., S.J.W., X.Y.Y., Z.Y., S.J.C., L.P., L.D., and X.A.N. performed all experiments. X.C.H. performed bioinformatics analysis. All authors were involved in the analysis and interpretation of the data.
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Zhang, YL., Sun, JW., Xie, YY. et al. Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. Cell Res 28, 476–490 (2018). https://doi.org/10.1038/s41422-018-0015-9
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DOI: https://doi.org/10.1038/s41422-018-0015-9
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