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Molecular targets for therapy

Restoration of MYC-repressed targets mediates the negative effects of GM-CSF on RUNX1-ETO leukemogenicity

Leukemia volume 31, pages 159–169 (2017)Cite this article

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Abstract

Granulocyte macrophage-colony-stimulating factor (GM-CSF) signaling regulates hematopoiesis and immune responses. CSF2RA, the gene encoding the α-subunit for GM-CSF, is significantly downregulated in t(8;21) (RUNX1-ETO or RE) leukemia patients, suggesting that it may serve as a tumor suppressor. We previously reported that GM-CSF signaling is inhibitory to RE leukemogenesis. Here we conducted gene expression profiling of primary RE hematopoietic stem/progenitor cells (HSPCs) treated with GM-CSF to elucidate the mechanisms mediating the negative effects of GM on RE leukemogenicity. We observed that GM treatment of RE HSPCs resulted in a unique gene expression profile that resembles primary human cells undergoing myelopoiesis, which was not observed in control HSPCs. Additionally, we discovered that GM-CSF signaling attenuates MYC-associated gene signatures in RE HSPCs. In agreement with this, a functional screen of a subset of GM-CSF-responsive genes demonstrated that a MYC inhibitor, MXI1 (Max interactor 1), reduced the leukemic potential of RE HSPCs and t(8;21) acute myeloid leukemia (AML) cells. Furthermore, MYC knockdown and treatment with the BET (bromodomain and extra terminal domain) inhibitor JQ1 reduced the leukemic potential of t(8;21) cell lines. Altogether, we discovered a novel molecular mechanism mediating the GM-CSF-induced reduction in leukemic potential of RE cells, and our findings support MYC inhibition as an effective strategy for reducing the leukemogenicity of t(8;21) AML.

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Acknowledgements

We thank the UC San Diego IGM Genomic Center for performing the microarray, as well as Dr Donna Neuberg and Dr Kristen Stevenson (Dana-Farber Cancer Institute) for advising with microarray data analysis. For flow cytometry expertise, we thank Dennis J Young of the UC San Diego Moores Cancer Center’s Flow Cytometry Shared Resource. Additionally, we also thank Dr Olivier Harismendy (UC San Diego) and Dr Kristin Jepsen (UC San Diego IGM Genomic Center) for their assistance with the barcode sequencing and data analysis. SW has received 2 years of fellowship support from the National Cancer Institute (NCI 5T32CA67754-17). Finally, we are very grateful to everyone in the Zhang Lab for helpful discussions. This work was supported by funding from the National Institutes of Health (NIH R01CA192924).

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  1. Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

    S Weng, S Matsuura, C T Mowery, S A Stoner, K Lam, D Ran, A G Davis, M-C Lo & D-E Zhang

  2. Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA

    D-E Zhang

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  1. S Weng
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Weng, S., Matsuura, S., Mowery, C. et al. Restoration of MYC-repressed targets mediates the negative effects of GM-CSF on RUNX1-ETO leukemogenicity. Leukemia 31, 159–169 (2017). https://doi.org/10.1038/leu.2016.167

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