Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy

Abstract

To turn a disease from highly fatal to highly curable is extremely difficult, especially when the disease is a type of cancer. However, we can gain some insight into how this can be done by looking back over the 50-year history of taming acute promyelocytic leukaemia (APL). APL is the M3 type of acute myeloid leukaemia characterized by an accumulation of abnormal promyelocytes in bone marrow, a severe bleeding tendency and the presence of the chromosomal translocation t(15;17) or variants. APL was considered the most fatal type of acute leukaemia five decades ago and the treatment of APL was a nightmare for physicians. Great efforts have been made by scientists worldwide to conquer this disease. The first use of chemotherapy (CT) was unsuccessful due to lack of supportive care and cytotoxic-agent-related exacerbated coagulopathy. The first breakthrough came from the use of anthracyclines which improved the complete remission (CR) rate, though the 5-year overall survival could only be attained in a small proportion of patients. A rational and intriguing hypothesis, to induce differentiation of APL cells rather than killing them, was raised in the 1970s. Laudably, the use of all-trans retinoic acid (ATRA) in treating APL resulted in terminal differentiation of APL cells and a 90-95% CR rate of patients, turning differentiation therapy in cancer treatment from hypothesis to practice. The combination of ATRA with CT further improved the 5-year overall survival. When arsenic trioxide (ATO) was used to treat relapsed APL not only the patients but also the ancient drug were revived. ATO exerts dose-dependent dual effects on APL cells: at low concentration, ATO induces partial differentiation, while at relatively high concentration, it triggers apoptosis. Of note, both ATRA and ATO trigger catabolism of the PML-RARalpha fusion protein which is the key player in APL leukaemogenesis generated from t(15;17), targeting the RARalpha (retinoic acid receptor alpha) or promyelocytic leukaemia (PML) moieties, respectively. Hence, in treating APL both ATRA and ATO represent paradigms for molecularly targeted therapy. At molecular level, ATRA and ATO synergistically modulate multiple downstream pathways/cascades. Strikingly, a clearance of PML-RARalpha transcript in an earlier and more thorough manner, and a higher quality remission and survival in newly diagnosed APL are achieved when ATRA is combined with ATO, as compared to either monotherapy, making APL a curable disease. Thus, the story of APL can serve as a model for the development of curative approaches for disease; it suggests that molecularly synergistic targeted therapies are powerful tools in cancer, and dissection of disease pathogenesis or anatomy of the cancer genome is critical in developing molecular target-based therapies.

Figure 1

Chromosomal translocations in APL.

Figure 2

The schematic represents induction of APL cell differentiation and apoptosis by ATRA and ATO. At pharmacological concentration (10⁻⁶ M), ATRA can induce degradation of the PML–RARα oncoprotein, leading to activation of repressed target genes. ATRA can also activate PML–RARα to recruit coactivators. A two-step model of promyelocytic differentiation is also shown. The first step is a priming for differentiation, presumably through derepression of PML/RARα repressed genes by ATRA. This can be bypassed by rexinoids. The second is maturation per se and can be induced by high doses of ATRA or differentiating agents such as cytokines or cAMP. ATO at low concentration induces partial differentiation of promyelocytes, while combined use of cAMP or cytokines can trigger terminal differentiation. The mature granulocytes can enter into programmed cell death. ATO can also induce apoptosis by targeting PML–RARα and activation of apoptotic machinery.

Figure 3

Ideogram illustration of dynamic changes underlying RA/ATO-induced differentiation/apoptosis in APL. Upregulated genes/proteins are marked in red whereas those downregulated are marked in blue. Synergistically/additively regulated genes/proteins are highlighted with a yellow background. Molecular events at the early, intermediate and late stages are rimmed by green, brown and blue lines, respectively. Intracellular compartments in which molecular events occur are also indicated in the ideogram.