The discovery of synergistic clinical activity between all-trans retinoic acid (RA) and chemotherapy has been remarkably successful in achieving about 70 percent long-term remissions, probable cures, in acute promyelocytic leukemia (APL). A major factor in achieving cure in the remaining 30 percent is the prevention of relapse, which is associated with APL cellular resistance to RA-induced differentiation in the majority of cases. Thus, this grant is directed at the two main outstanding problems: laboratory studies to predict the probability of clinical relapse allowing early intervention with potentially curative therapy and understanding the basis of the development of APL cellular RA-resistance. The first objective will be pursued in the context of a successor intergroup clinical trial (protocol C9710) for previously untreated APL in which the intergroup APL laboratory investigators will apply an advanced quantitative technique for monitoring minimal residual disease (MRD) in the hopes of defining criteria that will permit the reliable application of this methodology to direct future treatment decisions. The second objective will be pursued in three aims, one to further define the incidence and significance of the recent finding of one cause for APL cellular RA-resistance, mutations in the primary RA-response gene in APL cells, the PML-RARa fusion gene and two exploratory aims to try to identify alternative mechanisms of RA-resistance.
The specific aims are: (1) to perform diagnostic PML-RARalpha assays and to monitor minimal residual disease (MRD) by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) on Eastern Cooperative Oncology Group (ECOG) patients, as mandated on intergroup protocol C9710; (2) to further assess the importance of PML-RARalpha gene mutations in APL cellular RA-resistance; (3) to investigate the hypothesis that aberrations in proximate downstream transmitters of RA-mediated signals from PML-RARalpha, are involved in RA-resistance in some of the estimated two-thirds of cases of RA-resistance that do not involve mutations in PML-RARalpha; and (4) to investigate the hypothesis that there is an alternative, non-PML-RARalpha-mediated pathway for RA that may have a vital role in the initial APL cellular response to RA and that could be aberrant in some cases of RA-resistant relapse APL.
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