Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure

Abstract

Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.

The role of ubiquitination in tumorigenesis and targeted drug discovery

“…SUMOylation of PML recruits RNF4 and triggers its degradation in a ubiquitination-proteasome-dependent way. [106][107][108] Therefore, SUMOylation takes part in a variety of cellular physiological activities, such as gene stability maintenance and transcriptional regulation, and aberrant SUMOylation is closely related to the development and progression of certain diseases, including cancer.…”

Classic and Variants APLs, as Viewed from a Therapy Response

“…Multiple other features of PML-RARA were described, but their actual contributions to in vivo transformation remains unestablished. One of the most striking features of APL is its sensitivity to targeted therapies [6]. Indeed, APL has now become the most curable form of adult leukemia when treated by combined therapies with all trans-retinoic acid (ATRA) and arsenic trioxide (ATO).…”

“…Thus, ATRA and ATO are targeted therapies directed onto the two constitutive moieties of the PML-RARA fusion. The dual targeting of PML-RARA (for destruction) and PML (for NB formation prior to catabolism) explains the potency of single agent arsenic for APL [6,38].…”

“…The resulting chimeric PML-RARA protein ( Figure 1) promotes a clonal proliferation of myeloid precursors with a reduced differentiation capacity and acquisition of self-renewal. Pathogenesis of these "classic" APLs has been extensively reviewed elsewhere [6][7][8] and will only be sketched here. The World Health Organization (WHO) has revised the classification of AMLs, making APL with t(15; 17) (q24.1; q21.2), as a specific entity, but without taking in account the novel PML-independent RARs fusions [9].…”

Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies

“…Experimental strategies for the treatment of resistant APL Treatment outcomes in patients with newly diagnosed APL have improved dramatically in the last three decades since the advent of ATRA and, some years later, the introduction of ATO -ATRA combined with chemotherapy resulted in cure rates above 80%; but was associated with the risk of severe infections and secondary leukemias [98][99][100][101]. ATO has been shown to act synergistically with ATRA to induce the degradation of the PML-RARΑ oncoprotein [102] and the chemo-free ATRA-ATO approach is nowadays regarded as the first treatment choice for patients with nonhigh-risk APL [71,72,103]. A recent review from the European leukemia network details the guidelines in the management of frontline and relapsed APL and the specific recommendations for the identification and management of the most important complications: bleeding disorder, differentiation syndrome, QT prolongation and all the other toxicities related to treatment with ATRA and ATO [55] When diagnosed and treated promptly, APL is curable in the vast majority of patients, yet approximately 5 % of cases are resistant to standard therapy and 5 to 10% relapse and eventually become resistant (Coombs et al 2015).…”