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Stem Cells

PML–RARα initiates leukemia by conferring properties of self-renewal to committed promyelocytic progenitors

Leukemia volume 23, pages 1462–1471 (2009)Cite this article

Abstract

Acute promyelocytic leukemia (APL) is characterized by hyperproliferation of promyelocytes, progenitors that are committed to terminal differentiation into granulocytes, making it an ideal disease in which to study the transforming potential of less primitive cell types. We utilized a murine model of APL in which the PML–RARα oncogene is expressed from the endogenous cathepsin G promoter to test the hypothesis that leukemia stem cell (LSC) activity resides within the differentiated promyelocyte compartment. We prospectively purified promyelocytes from transgenic mice at various stages of disease and observed that PML–RARα-expressing promyelocytes from young preleukemic mice had acquired properties of self-renewal both in vitro and in vivo. Progression to acute leukemia was associated with an expansion of the promyelocyte compartment at the expense of other stem, progenitor and terminally differentiated populations. Leukemic promyelocytes exhibited properties of self-renewal, and were capable of engendering leukemia in secondary recipient mice. These data indicate that PML–RARα alone can confer properties of self-renewal to committed hematopoietic progenitors before the onset of disease. These findings are consistent with the hypothesis that cancer stem cells may arise from committed progenitors that lack stem cell properties, provided that the initiating mutation in cancer progression activates programs that confer properties of self-renewal.

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Acknowledgements

We thank Maricel Gozo and Dena Leeman for technical support, as well as Stefan Fröhling, Claudia Scholl and all the members of the Gilliland laboratory for helpful discussions and comments regarding this study. DGG is a Doris Duke Foundation Distinguished Clinical Scientist and a Howard Hughes Medical Institute investigator. Supported in part by National Institute of Health grants DK50654 and CA66996 and by the Leukemia and Lymphoma society to DGG.

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Authors and Affiliations

  1. Division of Hematology, Brigham and Women's Hospital, Boston, MA, USA

    S Wojiski, T Kindler, B H Lee, A Fabian & D G Gilliland

  2. Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA

    S Wojiski, T Kindler, B H Lee, A Fabian & D G Gilliland

  3. Department of Hematology/Oncology, Harvard Institutes of Medicine, Boston, MA, USA

    F C Guibal & D G Tenen

  4. Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    J L Jesneck

  5. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    J L Jesneck

  6. Harvard Stem Cell Institute, Harvard University, Boston, MA, USA

    D G Tenen & D G Gilliland

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  1. S Wojiski
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  2. F C Guibal
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Correspondence to D G Gilliland.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Wojiski, S., Guibal, F., Kindler, T. et al. PML–RARα initiates leukemia by conferring properties of self-renewal to committed promyelocytic progenitors. Leukemia 23, 1462–1471 (2009). https://doi.org/10.1038/leu.2009.63

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