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Pro-proliferative function of the long isoform of PML-RARα involved in acute promyelocytic leukemia

Oncogene volume 25, pages 3375–3386 (2006)Cite this article

Abstract

The promyelocytic leukemia (PML) gene codes for a tumor suppressor protein that is associated with distinct subnuclear macromolecular structures called the PML bodies. The PML gene is frequently involved in the t(15;17) chromosomal translocation of acute promyelocytic leukemia (APL). The translocation results in a fusion gene product, PML-RARα, in which the PML gene fuses to the retinoic acid receptor α (RARα) gene. PML-RARα has been shown to promote transcriptional repression of genes involved in myeloid terminal differentiation and to disrupt the architecture of PML bodies, a phenotype reversed by treatment with all trans retinoic acid (ATRA). However, there are several alternatively spliced isoforms of PML-RARα. Here, we addressed the differences between the short and the long isoforms of PML-RARα (L and S) since both are associated with APL. We demonstrate that PML-RARαL, but not PML-RARαS, can directly promote cell growth by transcriptionally activating the pro-proliferative gene, c-fos, in response to mitogenic stimulation. The activity of the PML-RARαL is completely sensitive to ATRA. We further show that this activation is not via direct recruitment of the protein to the c-fos promoter but indirectly by altering the chromosomal environment of the c-fos gene, thereby rendering it more accessible to the signal induced transcriptional activators. Our results suggest that in addition to antagonizing the PML-tumor suppressor or the PML-pro-apoptotic activity, PML-RARα proteins can also directly promote cell growth by activating c-fos.

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Acknowledgements

We thank Dr Pier Paolo Pandolfi for providing the PML and PML-RARαS isoform constructs. We thank Dr Donald Bloch for providing the PML-RARαL isoform construct. We thank Munya Al-Fulaij for the p(SRE)5-luc contruct. We also thank the Roy lab members for helpful discussions. We are particularly grateful to Edouard Vannier for help with the design of all real-time c-fos primers and probes. This work is supported in part by NIH grant (AI056240) to ALR.

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  1. Department of Pathology, Tufts University School of Medicine, Boston, MA, USA

    M I Tussié-Luna, L Rozo & A L Roy

  2. Program in Immunology, Tufts University School of Medicine, Boston, MA, USA

    A L Roy

  3. Program in Genetics, Tufts University School of Medicine, Boston, MA, USA

    A L Roy

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  1. M I Tussié-Luna
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  2. L Rozo
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Correspondence to A L Roy.

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Tussié-Luna, M., Rozo, L. & Roy, A. Pro-proliferative function of the long isoform of PML-RARα involved in acute promyelocytic leukemia. Oncogene 25, 3375–3386 (2006). https://doi.org/10.1038/sj.onc.1209388

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