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Oncogenes, Fusion Genes and Tumor Suppressor Genes

Notch signaling in acute promyelocytic leukemia

Leukemia volume 27, pages 1548–1557 (2013)Cite this article

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Abstract

Acute promyelocytic leukemia (APL) is initiated by the PML-RARA (PR) fusion oncogene and has a characteristic expression profile that includes high levels of the Notch ligand Jagged-1 (JAG1). In this study, we used a series of bioinformatic, in vitro, and in vivo assays to assess the role of Notch signaling in human APL samples, and in a PML-RARA knock-in mouse model of APL (Ctsg-PML-RARA). We identified a Notch expression signature in both human primary APL cells and in Kit+Lin−Sca1+ cells from pre-leukemic Ctsg-PML-RARA mice. Both genetic and pharmacologic inhibition of Notch signaling abrogated the enhanced self-renewal seen in hematopoietic stem/progenitor cells from pre-leukemic Ctsg-PML-RARA mice, but had no influence on cells from age-matched wild-type mice. In addition, six of nine murine APL tumors tested displayed diminished growth in vitro when Notch signaling was inhibited pharmacologically. Finally, we found that genetic inhibition of Notch signaling with a dominant-negative Mastermind-like protein reduced APL growth in vivo in a subset of tumors. These findings expand the role of Notch signaling in hematopoietic diseases, and further define the mechanistic events important for PML-RARA-mediated leukemogenesis.

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Acknowledgements

We thank Drs Raphael Kopan, Daniel Link, Matthew Walter, Jacqueline Payton, David H. Spencer and John Welch for assistance and/or helpful discussions. Mieke Hoock, Dan George and Nick Protopsaltis provided invaluable animal husbandry assistance, and Erin Wehmeyer provided excellent technical support. We are grateful to the Cancer Genome Atlas for access to the RNA-Seq data for JAG1. We thank the High Speed Cell Sorter Core, the Laboratory of Clinical Genomics, the Tissue Procurement Core and the Bioinformatics Core of the Siteman Cancer Center at Washington University for their assistance with this study. This work was supported by NIH R01 CA083962, NIH PO1 CA101937 and the Barnes Jewish Hospital Foundation (all to TJL), NIH T32 HL007088-35 (NRG) and the Doris Duke Charitable Foundation to Washington University (SMS, Clinical Research Fellow).

Author Contributions

NRG, JMK and TJL designed the research, analyzed data and wrote the paper; TL, AMV, LDW and SMS performed experiments.

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Author notes

  1. N R Grieselhuber and J M Klco: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Oncology, Department of Medicine, Section of Stem Cell Biology, Washington University School of Medicine, St Louis, MO, USA

    N R Grieselhuber, A M Verdoni, T Lamprecht, S M Sarkaria, L D Wartman & T J Ley

  2. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA

    J M Klco

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  1. N R Grieselhuber
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  2. J M Klco
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  3. A M Verdoni
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Correspondence to T J Ley.

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Grieselhuber, N., Klco, J., Verdoni, A. et al. Notch signaling in acute promyelocytic leukemia. Leukemia 27, 1548–1557 (2013). https://doi.org/10.1038/leu.2013.68

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