Kim Rice

Acute promyelocytic leukaemia (APL) biology started by the discovery of the driving t(15;17) translocation in 1977, followed by the unexpected ex vivo differentiation by a hormone, retinoic acid (RA), and the miraculous complete remissions that this drug yields in patients. This led to 25 years of extensive molecular explorations of the pathogenesis of this disease, starting with the identification of the retinoic acid receptor alpha (RARA) as the central target of all APL-associated translocations. The t(15;17) translocation associated with over 98 % of APL drives the expression of the PML-RARA fusion protein. The clinical activity of RA in a disease caused by an altered retinoic acid receptor constituted the first example of targeted therapy. How PML-RARA blocks differentiation and promotes self-renewal, but also how it confers RA-sensitivity, was the focus of intense investigations. While the first models emphasized the key role of transcriptional repression of RARA targets and subsequent reactivation by RA, further studies performed in animal models progressively lent weight to interference with PML function in transformation and PML-RARA degradation by RA in therapy response. The central role of PML-RARA degradation in therapy response was further supported by the discovery of the therapeutic activity of arsenic, a highly efficient APL drug, which also initiates PML-RARA degradation by targeting the PML moiety. Many studies investigated the pathogenesis of the most common variant t(11;17) translocations that yield a PLZF/RARA fusion. These rare APLs are distinctly much less sensitive to RA and completely resistant to arsenic. Finally, based on mouse models, clinical trials associating frontline RA and arsenic have demonstrated an extraordinary potency, definitively curing almost all cases of standard risk APL without any chemotherapy. Thus, through decades of basic research, cytogenetic analysis paved the way for the identification of the key PML-RARA driver, and molecular modelling of APL pathogenesis ultimately led to cure.