Molecular Mechanisms of Acute Promyelocytic Leukemia

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DESCRIPTION (provided by applicant): The promyelocytic leukemia (PML) gene codes for a tumor suppressor protein that is associated with distinct subnuclear macromolecular structures called the PML bodies. The PML gene is frequently involved in the t (15;17) chromosomal translocation of acute promyelocytic leukemia (APL). The translocation results in a fusion gene product, PML-RARalpha, in which the PML gene fuses to the retinoic acid receptor alpha (RARalpha) gene. PML-RARa behaves as a potent transcriptional repressor for apoptotic genes and disrupts the architecture of PML bodies, a phenotype reversed by treatment with all trans retinoic acid (ATRA). Besides its role in APL, PML bodies have also been linked to viral infection. A variety of viruses targets the nuclear bodies and often causes their disruption. Moreover, upon interferon treatment of normal cells, PML is induced and the number of PML bodies increases dramatically, suggesting that PML may function as a mediator of interferon function and behaves as an immune surveillance factor. Although the activities of several transcription factors are modulated by virtue of physical association with PML bodies, the molecular mechanisms of PML or PML-RARalpha-mediated gene regulation remain elusive. Given the biological importance of PML and PML-RARalpha proteins, it is critical to ascertain their functional role and mechanisms of action. The TFII-I family of multifunctional transcription factors is activated in response to growth factor and antigenic signals to regulate growth-controlling genes, thus linking signal transduction events to transcription. We show a novel association of TFII-I family of factors with PML bodies. We further show a previously unknown function for PML-RARalpha it hyper-activates c-fos promoter in response to growth factor signaling. Based on these and other results, we hypothesize that the growth-regulatory and antigenic signals are processed through PML bodies in normal and APL cells to activate genes that control cellular growth or death via TFII-I family proteins. We propose to elucidate this novel pathway that will lead to a better understanding of PML and PML-RARalpha function.