The past 20 years have brought unprecedented improvements in the clinical management of cancers. Many targeted therapies against cancer are aimed at inhibiting the enzymatic activity of kinases or at antibody-induced neutralizations of growth-promoting receptors. Yet, they rarely achieve cure. APL (Acute Promyelocytic Leukemia) is an aggressive cancer and a rare example in which targeted therapy has led to definitive cures through full degradation of the driving oncoprotein, PML/RARA 1, 2. APL cure is a milestone achievement in translational medicine 3, 4, 5. The PML (promyelocytic leukemia) protein, a fusion partner in PML/RARA, is a tumor suppressor and the master organizer of PML nuclear bodies (NBs). NBs are nuclear organelles that recruit hundreds of functionally diverse partner proteins, including transcription factors such as P53, DNA repair proteins and enzymes 6, 7. PML fine-tunes key cellular functions such as apoptosis/senescence, stem cell self-renewal, anti-viral immunity, stress response and metabolism. In APL, NBs are disrupted in a therapy-reversible manner. Therapy enforced NB reformation underlies the basis of APL cure. It is now widely accepted that PML has tumor suppressive functions beyond APL and the hematopoietic system. Most solid tumors display PML loss or down-regulation. Understanding the functions and regulation of PML and PML NBs has become the focus of intense research 8.Post-translational modifications (PTMs) dynamically tune protein function and stability. Based on our recent data, PML NBs emerge as cellular factories of protein sumoylation and SUMO-initiated secondary PTMs, most notably ubiquitination/degradation 9. Our findings point at the existence of an integrated circuit where distinct signals or stresses (input) are processed in PML NBs (via induction of partner sumoylation and secondary PTMs) to culminate in a specific biological response (output, i.e. tumor suppression) 10, 7. Critically, NB-mediated sumoylation/ubiquitination/degradation can be harvested pharmacologically to eliminate toxic, malignant or viral proteins for clinical management of diverse pathologies, including cancers. Combination therapies involving PML- and SUMO-inducing agents (i.e. arsenic, interferons, retinoic acid) efficiently drive full destruction of undesired proteins in situ in PML NBs. Such therapies can also activate, via PML NBs, a P53/senescence axis, eradicating unhealthy or cancerous cells 11, 12, 6, 7.Indeed, by manipulating this integrated circuit using an arsenic/interferon-based combination therapy, we achieved full in situ destruction of the HTLV1 Tax oncoprotein in NBs, and definitively cured Adult T-Cell Lymphoma (ATL) in HTLV1-infected patients, otherwise a fatal, chemotherapy-resistant cancer 13.Collectively, our findings demonstrate the clinical feasibility of PML/SUMO-enforced therapies. PML expression, which is diminished in cancers, can be restored pharmacologically to induce NB reformation and reactivate tumor suppression 14. Simultaneously, cancer-driving oncoproteins can be cleared in situ in NBs to eradicate cancer stem cells. Our strategy is also applicable to neurodegenerative diseases where toxic or poly-glutamine protein aggregates can be cleared in NBs pharmacologically. Such aggregates accumulate in and overload PML NBs in decaying neurons, and we are also interested in exploring whether disrupted NB function per se contributes to neurodegeneration. Finally, as both PML and SUMOs are critical regulators of self-renewal and pluripotency, our findings have important implications for development, stem cell biology and regenerative medicine 15, 7. 

Further reading:1) de Thé, 1990, Nature (PMID: 2170850)2) de Thé, 1991, Cell (PMID: 1652369)3) de Thé, 2010, Nat Rev Cancer (PMID: 20966922) 4) de Thé, 2012, J Cell Biol (PMID: 22778276)5) Lallemand-Breitenbach, 2013, Blood (PMID: 23894153)6) Sahin, 2014, Nucleus (PMID: 25482067)7) Sahin, 2014, J Pathol (PMID: 25138686)8) Bernardi, 2007, Nat Rev Mol Cell Biol (PMID: 17928811)9) Sahin, 2014, J Cell Biol (PMID: 24637324)10) Sahin, 2014, Nat Commun (PMID: 24942926)11) Ablain, 2014, Nat Med (PMID: 24412926)12) Lehmann-Che, 2014, N Eng J Med (PMID: 25229938)13) Dassouki/Sahin (equal contribution), 2015, Blood (PMID: 25395419)14) Lallemand-Breitenbach, 2006, Cell (PMID : 16873055)15) Lallemand-Breitenbach, 2012, Cell Stem Cell (PMID : 23040473)