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

Tussié-Luna, M I
Rozo, L
Roy, A L

¹Department of Pathology, Tufts University School of Medicine, Boston, MA, USA; ²Program in Immunology, Tufts University School of Medicine, Boston, MA, USA and ³Program in Genetics, Tufts University School of Medicine, Boston, MA, USA

Oncogene (2006) 25, 3375-3386. doi:10.1038/sj.onc.1209388

Correspondence: Dr AL Roy, Department of Pathology, Tufts University School of Medicine, 150 Harrison Avenue, Boston, MA 2111, USA. E-mail: [email protected]

Received 28 July 2005; revised 11 November 2005; accepted 7 December 2005; published online 23 January 2006

Oncogene 25(24):p 3375-3386, June 8, 2006.

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.