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Acute Leukemias

The self-association coiled-coil domain of PML is sufficient for the oncogenic conversion of the retinoic acid receptor (RAR) alpha

Leukemia volume 25, pages 814–820 (2011)Cite this article

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Abstract

In acute promyelocytic leukemia (APL) the retinoic acid receptor alpha (RARα) becomes an oncogene through the fusion with several partners, mostly with promyelocytic leukemia protein (PML), all of which have in common the presence of a self-association domain. The new fusion proteins, therefore, differently from the wild-type RARα, which forms only heterodimers with retinoic X receptor alpha, are also able to homo-oligomerize. The presence of such a domain has been suggested to be crucial for the leukemogenic potential of the chimeric proteins found in APL blasts. Whether or not any self-association domain is sufficient to bestow a leukemogenic activity on RARα is still under investigation. In this work, we address this question using two different X-RARα chimeras, where X represents the coiled-coil domain of PML (CC-RARα) or the oligomerization portion of the yeast transcription factor GCN4 (GCN4–RARα). We demonstrate that in vitro both proteins have transforming potential, and recapitulate the main PML–RARα biological properties, but CC-RARα is uniquely able to disrupt PML nuclear bodies. Indeed, in vivo only the CC-RARα chimera induces efficiently APL in a murine transplantation model. Thus, the PML CC domain represents the minimal structural determinant indispensable to transform RARα into an oncogenic protein.

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Acknowledgements

We thank Massimo Stendardo, Manuela Capillo and the IFOM-IEO Campus mouse-service for the help with mice; tissue culture, sequencing, imaging and molecular pathology facilities for the technical assistance; Francesca Refaldi, Marco Sconfietti, Chiara Saccomanni and Anna Sciullo for cell sorting and FACS analysis; Sebastiano Pasqualato for SEC experiments. We thank Winfried Weissenhorn for the gift of the GCN4 encoding plasmid. We are grateful to Andrea Musacchio, Claudio Ciferri and Oronzina Botrugno for helpful discussions; Francesca De Franco, Roberto Dal Zuffo, Alessandra Marinelli, Virginia Giuliani, Sara Barozzi, and Mauro Romanenghi for technical support. Work in SM lab is supported by: AIRC, EEC (Epitron), Cariplo, MIUR, MiS.

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Author notes

  1. M Occhionorelli

    Present address: 5Present address: Department of Molecular Oncology, Fondazione San Raffaele del Monte Tabor, via Olgettina 60, Milan 20132, Italy.,

  2. A Viale

    Present address: 6Present address: Dana-Farber Cancer Institute, Department of Medical Oncology, 44 Binney Street, Mayer 413, Boston, MA 02115, USA.,

  3. M Occhionorelli and F Santoro: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Oncology, IFOM-IEO Campus, Milan, Italy

    M Occhionorelli, F Santoro, I Pallavicini, A Gruszka, S Moretti, D Bossi, A Viale, D Shing, S Ronzoni, I Muradore, M Soncini, P G Pelicci & S Minucci

  2. Department of Anatomic Pathology, European Institute of Oncology (IEO), Milan, Italy

    G Pruneri, P Rafaniello & G Viale

  3. Department of Medicina, Chirurgia e Odontoiatria, University of Milan, Milan, Italy

    P G Pelicci

  4. Department of Biomolecular Sciences and Biotechnology, University of Milan, Milan, Italy

    S Minucci

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Correspondence to F Santoro or S Minucci.

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Occhionorelli, M., Santoro, F., Pallavicini, I. et al. The self-association coiled-coil domain of PML is sufficient for the oncogenic conversion of the retinoic acid receptor (RAR) alpha. Leukemia 25, 814–820 (2011). https://doi.org/10.1038/leu.2011.18

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