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Stem Cells

Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells

Leukemia volume 28, pages 1081–1091 (2014)Cite this article

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Abstract

Through a targeted knockdown (KD) screen of chromatin regulatory genes, we identified the EP400 complex components EPC1 and EPC2 as critical oncogenic cofactors in acute myeloid leukemia (AML). EPC1 and EPC2 were required for the clonogenic potential of human AML cells of multiple molecular subtypes. Focusing on MLL-mutated AML as an exemplar, Epc1 or Epc2 KD-induced apoptosis of murine MLL-AF9 AML cells and abolished leukemia stem cell potential. By contrast, normal hematopoietic stem and progenitor cells (HSPC) were spared. Similar selectivity was observed for human primary AML cells versus normal CD34+ HSPC. In keeping with these distinct functional consequences, Epc1 or Epc2 KD-induced divergent transcriptional consequences in murine MLL-AF9 granulocyte-macrophage progenitor-like (GMP) cells versus normal GMP, with a signature of increased MYC activity in leukemic but not normal cells. This was caused by accumulation of MYC protein and was also observed following KD of other EP400 complex genes. Pharmacological inhibition of MYC:MAX dimerization, or concomitant MYC KD, reduced apoptosis following EPC1 KD, linking the accumulation of MYC to cell death. Therefore, EPC1 and EPC2 are components of a complex that directly or indirectly serves to prevent MYC accumulation and AML cell apoptosis, thus sustaining oncogenic potential.

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Acknowledgements

We thank Jodie Whitaker, Gillian Newton, Morgan Blaylock, Jeff Barry, Michael Hughes, Gail Bruder, Angela Cooke and Deepti Wilks for technical support; William Harris for assistance with plasmid preparations; Chris Womack and staff at the Clinical Pharmacology Unit at Astra Zeneca, Alderley Park, UK for access to normal subjects for BM collection; and Georges Lacaud, Nullin Divecha and Valerie Kouskoff for a critical reading of the manuscript. This work was supported by Cancer Research UK grant number C5759/A12328.

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  1. Leukemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK

    X Huang, G J Spencer, J T Lynch, F Ciceri, T D D Somerville & T C P Somervaille

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  1. X Huang
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Correspondence to T C P Somervaille.

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Huang, X., Spencer, G., Lynch, J. et al. Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells. Leukemia 28, 1081–1091 (2014). https://doi.org/10.1038/leu.2013.316

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