How Arsenic Can Cure One Type Of Leukemia

Arsenic is a poison which has been used in medicine for more than 3000 years.  It is now regularly used to treat acute promyelocytic leukemia. This type of leukemia is characterized by the fusion of PML and RARA proteins, which is sufficient to make cells leukemic. Earlier, Pr. Hugues de Thé’s team had shown that arsenic induces the SUMOylation of PML/RARA, SUMO being a peptide that regulates interaction between proteins.  But the nature of the degradation pathway remained a mystery, because SUMO generally works against degradation.

A new enzyme which participates in this mechanism, RNF4, has recently been identified by the researchers. This enzyme plays a key role in the recognition and degradation of PML/RARA forms which have been modified by arsenic (PML/RARA-SUMO). The work of the French team, like that of an English team publishing in the same journal, shows that RNF4 binds to PML-SUMO or PML/RARA-SUMO. It then fixes another peptide, ubiquitin, onto this complex.  Ubiquitin is known to lead to the degradation of proteins to which is binds.  Ubiquitin then modifies the PML/RARA-SUMO protein.

The existence of a degradation pathway, initiated by SUMO and completed by ubiquitin, had been predicted by genetic studies on yeast, but no susbtrate had been identified. This research should lead to a better understanding of the molecular bases for therapy, and to better strategies for treating this illness.

Journal reference : Arsenic degrades PML or PML-RARA through a SUMO-triggered RNF4/ubiquitin-mediated pathway, Lallemand-Breitenbach, V., Jeanne, M., Benhenda, S., Nasr, R., Lei, M., Peres, L., Zhou, J., Zhu, J., Raught, B., and de The, H., Nature Cell Biology, 13 April 2008 (online)