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Cytogenetics and molecular genetics

Loss of Dnmt3b accelerates MLL-AF9 leukemia progression

Leukemia volume 30, pages 2373–2384 (2016)Cite this article

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Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic disorder with a poor prognosis. Abnormal DNA methylation is involved in the initiation and progression of AML. The de novo methyltransferases Dnmt3a and Dnmt3b are responsible for the generation of genomic methylation patterns. While DNMT3A is frequently mutated in hematological malignancies, DNMT3B is rarely mutated. Although it has been previously reported that Dnmt3b functions as a tumor suppressor in a mouse model of Myc-induced lymphomagenesis, its function in AML is yet to be determined. In this study, we demonstrated that deletion of Dnmt3b accelerated the progression of MLL-AF9 leukemia by increasing stemness and enhancing cell cycle progression. Gene profiling analysis revealed upregulation of the oncogenic gene set and downregulation of the cell differentiation gene set. Furthermore, loss of Dnmt3b was able to synergize with Dnmt3a deficiency in leukemia development. Taken together, these results demonstrate that Dnmt3b plays a tumor suppressive role in MLL-AF9 AML progression, thereby providing new insights into the roles of DNA methylation in leukemia development.

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Acknowledgements

We thank Dr Hideo Ema and Yajing Chu for their valuable suggestions for our experiments and critical reading for our manuscript. We are also grateful to our laboratory members and collaborators for their insightful discussion during the course of this work and in the preparation of the manuscript. This work was supported by grants the Ministry of Science and Technology of China (2016ZY05002341, 2011CB964800, 2013CB966902, 2015CB964400), and the National Natural Science Foundation of China (81421002, 81430004, 81330015, 91519315, 81300374, 81300375, 81400077, 81500085).

Author contributions

YZ designed and performed the experiments, analyzed the data and wrote the manuscript. HZ helped with all experiments and assisted with the manuscript. XL performed the methylation analyses. YW and PL helped with the mouse experiments and flow cytometry. FD, YP, SM and HC helped with the data analysis and assisted with the manuscript. SH, FT, WY and XZ conducted the research, analyzed the data and assisted with the manuscript. TC conceived the study, designed the experiments, interpreted the results, wrote the paper and oversaw the research project.

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Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

    Y Zheng, H Zhang, Y Wang, P Lu, F Dong, Y Pang, S Ma, H Cheng, S Hao, W Yuan, X Zhang & T Cheng

  2. Department of Medicine, Loma Linda University, Loma Linda, CA, USA

    X Zhang

  3. Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing, China

    X Li & F Tang

  4. Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Peking University, Beijing, China

    F Tang

  5. Department of Stem Cell and Regenerative Medicine, Peking Union Medical College, Tianjin, China

    W Yuan, X Zhang & T Cheng

  6. Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China

    W Yuan & T Cheng

  7. Collaborative Innovation Center for Cancer Medicine, Tianjin, China

    T Cheng

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Zheng, Y., Zhang, H., Wang, Y. et al. Loss of Dnmt3b accelerates MLL-AF9 leukemia progression. Leukemia 30, 2373–2384 (2016). https://doi.org/10.1038/leu.2016.112

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