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

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-RAR alpha, in which the PML gene fuses to the retinoic acid receptor alpha (RAR alpha) gene. PML-RAR alpha 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-RAR alpha. Here, we addressed the differences between the short and the long isoforms of PML-RAR alpha (L and S) since both are associated with APL. We demonstrate that PML-RAR alpha L, but not PML-RAR alpha S, can directly promote cell growth by transcriptionally activating the pro-proliferative gene, c-fos, in response to mitogenic stimulation. The activity of the PML-RAR alpha L 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-RAR alpha proteins can also directly promote cell growth by activating c-fos.