Assessment of Clinical Retinoid Activity in Leukemia

Montefiore Medical Center (Bronx, Ny), New York NY

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Abstract

DESCRIPTION (provided by applicant): The discovery of synergistic clinical activity between all-trans retinoic acid (RA) and chemotherapy has been remarkably successful in achieving about 70% long-term remissions, probable cures, in acute promyelocytic leukemia (APL). A major factor in achieving cure in the remaining 30% is the prevention of relapse, which we have determined is associated with APL cellular resistance to RA-induced differentiation in the majority of cases. Thus, this grant is primarily directed at the two main outstanding problems: laboratory studies to predict the prospect 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 is being pursued in the context of an intergroup clinical trial (C9710) for previously untreated APL involving the application of real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) technology for monitoring minimal residual disease (MRD), in part based on results from completion of a similar project linked to the prior intergroup APL trial (E2491). Funding of this aim was previously approved for non-competitive renewal for 2 additional years to coincide with the projected term of protocol 09710. The second objective will be pursued in two aims, which have been revised based on considerations that alternative approaches are required to relate mutations in the PML-RARa gene to clinical RA-resistance and, as proposed in the previous competitive grant submission, that complex alternative retinoid molecular response pathways may be contributory to RA-resistance and may lead to alternative treatment strategies. A key ingredient in the investigative strategy is our establishment of a new APL cell line, AP-1060, that, related to a mutation in the AF-2 region of PML-RARa, has RA-response characteristics likely of unusual value for dissecting alternative retinoid response pathways and their possible inter-relationship. Additionally, in recognition of evidence that unidentified mutations other than PML-RARa are required for APL pathogenesis, we propose to identify the genes involved in the single additional karyotypic abnormality, i.e., in addition to the APL-specific t(15;17), in AP-1060 cells, a t(3;14)(p21.1;q11.2), which we hypothesize produces novel gene abnormalities related to the enhanced growth characteristics of the AP-1060 cells that may, more generally, be related to progression-related molecular disturbances in APL and other malignancies.