Identification of the t(15;17) in AML FAB types other than M3: evaluation of the role of molecular screening for the PML/RARalpha rearrangement in newly diagnosed AML

Acute promyelocytic leukaemia (APL) is characterized by the t(15;17) leading to the formation of PML-RARα and RARα-PML fusion genes; this rearrangement has been considered both diagnostic for, and restricted to, this subtype of acute myeloid leukaemia (AML FAB M3). We describe two cases of AML with the t(15;17) associated with a PML/RARα rearrangement which lacked typical APL morphology, classified as FAB M1 and M2 respectively. In both cases morphological review revealed small populations of cells which exhibited some features associated with APL. In the case classified as M1, PML immunofluorescence studies revealed the classic microparticulate nuclear staining pattern as observed in typical cases of APL with the t(15;17). Similarly, blasts from this case were found to be sensitive to ATRA in vitro as determined by NBT reduction test and by normalization of the PML nuclear body staining pattern. To determine the frequency of PML/RARα rearrangements in FAB subtypes other than M3, 530 patients from the MRC AML trials were screened using nested RT-PCR. Only one individual, initially classified as M5 with a normal karyotype, was found to have a PML/RARα rearrangement. The diagnosis was revised to M3 variant on subsequent morphological review. In conclusion, this study demonstrates that, in rare cases, the t(15;17) is not restricted to patients with M3 morphology as defined by current FAB criteria. Therefore, although we consider cytogenetic analysis of newly diagnosed cases of AML to be mandatory, our data suggests that routine molecular screening for PML/RARα rearrangements is not justified and should be reserved for those cases displaying features which may be suspicious of APL even if such cells comprise only a minority of the total population

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

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–RARα fusion protein which is the key player in APL leukaemogenesis generated from t(15;17), targeting the RARα (retinoic acid receptor α) 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–RARα 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