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Redundant function of retinoic acid receptor isoforms in leukemogenesis unravels a prominent function of genome topology and architecture in the selection of mutagenic events in cancer

Leukemia volume 23, pages 417–419 (2009)Cite this article

Retinoic acid receptors (RARs) are members of a much larger group of ligand-dependent transcription factors, the so-called nuclear receptors. In mammals, there are three distinct RAR subtypes: RARα, RARβ and RARγ.1 RARs share a high sequence homology, but show distinct transcriptional properties and expression pattern, suggesting similar but not necessarily overlapping functions. In haematopoietic differentiation, for example, the function of RARγ is uniquely required to maintain the stem cell compartment, whereas RARα seems to work primarily at later stages, favouring differentiation.2 In acute promyelocytic leukaemia (APL), chromosomal translocations involve in 100% of cases the α-subtype of the RAR gene (RARα), on chromosome 17. These translocations lead to the synthesis of chimeric proteins: in 95% of the cases, the translocation partner is the PML (promyelocytic leukaemia) gene on chromosome 15, leading to the formation of PML–RARα fusion gene.3 Both in vitro and in vivo studies have well defined the oncogenic roles of PML–RARα fusion protein in the pathogenesis of APL, acting as an altered RAR.4 In our previous work, we studied the transcriptional and biological properties of chimeric constructs where PML was fused to RARβ or RARγ to generate the PML–RARβ and PML–RARγ fusion proteins (which do not exist in nature). Both chimeric proteins demonstrated similar properties to PML–RARα in vitro.5 Here, we extended this analysis to determine directly whether PML–RARγ (as a test case), like PML–RARα, is able to induce APL.

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  1. A Marinelli and D Bossi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biomolecular Sciences and Biotechnologies, University of Milan, Milan, Italy

    A Marinelli & S Minucci

  2. Department of Experimental Oncology, European Institute of Oncology, Milan, Italy

    D Bossi, P G Pelicci & S Minucci

  3. Department of Medicine, Surgery and Odontoiatry, University of Milan, Milan, Italy

    P G Pelicci

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  1. A Marinelli
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  2. D Bossi
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  3. P G Pelicci
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  4. S Minucci
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Correspondence to S Minucci.

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Marinelli, A., Bossi, D., Pelicci, P. et al. Redundant function of retinoic acid receptor isoforms in leukemogenesis unravels a prominent function of genome topology and architecture in the selection of mutagenic events in cancer. Leukemia 23, 417–419 (2009). https://doi.org/10.1038/leu.2008.205

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