Myelodysplastic syndrome

Loss of p300 accelerates MDS-associated leukemogenesis

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Abstract

The role that changes in DNA methylation and histone modifications have in human malignancies is poorly understood. p300 and CREB-binding protein (CBP), two distinct but highly homologous lysine acetyltransferases, are mutated in several cancers, suggesting their role as tumor suppressors. In the current study, we found that deletion of p300, but not CBP, markedly accelerated the leukemogenesis ofNup98-HoxD13 (NHD13) transgenic mice, an animal model that phenotypically copies human myelodysplastic syndrome (MDS). p300 deletion restored the ability of NHD13 expressing hematopoietic stem and progenitor cells (HSPCs) to self-renew in vitro, and to expand in vivo, with an increase in stem cell symmetric self-renewal divisions and a decrease in apoptosis. Furthermore, loss of p300, but not CBP, promoted cytokine signaling, including enhanced activation of the MAPK and JAK/STAT pathways in the HSPC compartment. Altogether, our data indicate that p300 has a pivotal role in blocking the transformation of MDS to acute myeloid leukemia, a role distinct from that of CBP.

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Acknowledgements

We thank the members of the Nimer lab for their assistance and thoughtful input. We thank the Sylvester Comprehensive Cancer Center Flow Cytometry and Oncogenomics Core Facilities helping carry out this work. We also thank Delphine Prou for her assistance in preparing this manuscript. This work was supported by National Cancer Institute Grant R01 CA166835-01 (SN). Shiekhattar’s laboratory was supported by R01 GM078455 and R01 GM105754 from the National Institute of Health and Sylvester Comprehensive Cancer Center.

Author contributions

SDN supervised the project. GC designed and performed most of the experiments, analyzed the data and wrote the manuscript; F Liu analyzed the data and revised the manuscript; TA, MN and F Lai performed some of the experiments and analyzed the data; HX generated the mouse colonies. SC, SG, PJH, KA, CM, MT and LW helped with some of the experiments.

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Correspondence to S D Nimer.

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The authors declare no conflict of interest.

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Cheng, G., Liu, F., Asai, T. et al. Loss of p300 accelerates MDS-associated leukemogenesis. Leukemia 31, 1382–1390 (2017) doi:10.1038/leu.2016.347

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