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Myelodysplastic syndrome

Utx loss causes myeloid transformation

Leukemia volume 32, pages 1458–1465 (2018)Cite this article

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Abstract

Recurrent somatic loss-of-function mutations in histone demethylases are frequently detected in cancer. However, whether loss of a histone demethylase can cause cancer has not been determined. Here, we report that knockout of the histone demethylase Utx in mice causes a chronic myelomonocytic leukemia (CMML)-like disease with splenomegaly, monocytosis, and extramedullary hematopoiesis. Mutational analysis of patient data indicated that UTX mutations occur simultaneously with TP53 mutations in myeloid malignancies, and combined inactivation of Utx and Trp53 accelerated the development of CMML in a cell-autonomous manner. Utx loss caused increased self-renewal of hematopoietic stem cells and predisposed hematopoietic stem cells to differentiate into myeloid-derived lineages. Transcriptome and chromatin immunoprecipitation analyses revealed that Utx activates key transcriptional factors required for erythroid differentiation by modulating histone H3 lysine 27 and lysine 4 trimethylation. Our results suggest that Utx suppresses CMML formation by controlling hematopoietic stem cell self-renewal and differentiation.

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Acknowledgements

We thank Lijian Hui (SIBCB, Shanghai, China) for sharing p53 KO mice. This work was supported by the National Basic Research Program of China (2014CB943100), the National Natural Science Foundation of China (81772472), and the “Strategic Priority Research Program” of the Chinese Academy of Sciences (XDB19000000). Accession numbers: RNA-Seq data are available in the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/) under the accession numbers: GSE97737.

Author contributions

LTZ and LYX designed and performed the experiments and wrote the manuscript. QX, DFZ, and GH performed the animal experiments. LY performed the bioinformatic analyses. PC analyzed the mouse phenotype. WW and YQW performed the cell experiments. CDC conceived and supervised the project and revised the manuscript.

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    Authors and Affiliations

    1. State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China

      Liting Zheng, Longyong Xu, Qing Xu, Lu Yu, Danfeng Zhao, Wei Wang, Yiqin Wang, Gang Han & Charlie Degui Chen

    2. Department of Laboratory Medicine, Zhongshan Hospital Fudan University, 180 Fenglin Road, 200032, Shanghai, China

      Pu Chen

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    Liting Zheng and Longyong Xu contributed equally to this work.

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    Zheng, L., Xu, L., Xu, Q. et al. Utx loss causes myeloid transformation. Leukemia 32, 1458–1465 (2018). https://doi.org/10.1038/s41375-018-0011-6

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