Acute promyelocytic leukemia (APL) is a form of acute myeloid leukemia (AML) associated with fusion of the retinoic acid receptor alpha gene with the gene encoding the PML nuclear protein. In APL, the leukemic cells are blocked at the promyelocyte stage of differentiation but can be induced to develop into mature neutrophils by treatment with retinoic acid. The use of retinoic acid to treat APL is a successful example of molecularly-targeted cancer therapy. The broad long-term objectives of the proposed work are to identify the combinations of genetic changes that result in AML and to delineate the mechanisms by which these changes transform normal blood cells into leukemias. The ultimate goal is to utilize this knowledge to improve treatment for human patients with leukemias and other malignancies. The specific research proposed in this application utilizes murine models of leukemia to (i) identify activities of the fusion protein PMLRARalpha that contribute to leukemogenesis and (ii) identify the molecular events that cooperate with PMLRARalpha in leukemogenesis. Activities of PMLRARalpha that may contribute to leukemia are abrogation of the normal function of PML and disruption of normal transcription in myeloid cells (including transcriptional repression of retinoic acid responsive target genes as well as inhibition of other transcription factors). The contribution of activities of PMLRARalpha to leukemogenesis will be assessed by expressing altered forms of PMLRARalpha in mice mutant versions of PMLRARalpha differentially impaired for specific functions will be tested for their ability to initiate leukemia. The development of novel retroviral-based models of APL to complement work with transgenic mice should facilitate assessment of the leukemogenic potential of these altered forms of PMLRARalpha. Additional changes that cooperate with PMLRARalpha are required for leukemogenesis in transgenic mice. Although the nature of these cooperating events is not clear, activation of growth factor receptors may contribute to leukemia. This hypothesis will be assessed by transducing PMLRARalpha-expressing bone marrow cells with retroviral vectors that drive expression of activated forms of IL-3 receptor or activated FLT3. Further, various mutant forms of activated receptors will be compared in regard to their ability to cooperate with PMLRARalpha. Correlating the ability of these mutants to cause leukemia with their different effects on growth factor signaling pathways should identify downstream events that have a central role in transformation. In addition, by examining whether the expression or activity of candidate mediators is abnormal in leukemic cells, molecules that participate in the pre-leukemia to leukemia transition will be delineated. The proposed studies should identify molecular pathways and particular molecules that are central to the pathogenesis of AML. This work will aid the development of new molecularly-targeted treatments for these malignancies.
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