In this issue, Kawasaki and colleagues (page 3668) demonstrate that the nuclear-matrix–associated protein, promyelocytic leukemia protein (PML), binds to and inhibits Stat3 transcriptional activity. The region of Stat3 bound by PML includes its DNA binding domain. Overexpression of PML inhibited ligand-activated Stat3 DNA binding, suggesting that PML may decrease Stat3 transcriptional activity, at least in part, through this mechanism. The authors also demonstrate that the fusion gene product PML-RARα, which results from t(15, 17) in acute promyelocytic leukemia (APL), enhances Stat3 transcriptional activity, confirming the findings of our group regarding cross talk between Stat3 and APL fusion proteins including PML-RARα (Dong and Tweardy, Blood. 2002;99:2637-2646). They also extend these findings in important ways by demonstrating that the enhanced activity of Stat3 by PML-RARα is mediated, in part, by release of PML suppression of Stat3 activity and demonstrating that these effects on Stat3 are biologically relevant: Stat3dependent growth of Ba/F3 cells was inhibited by PML and enhanced by PML-RARα.
APL cells are characterized by a block in myeloid differentiation at the promyelocytic stage and by resistance to apoptosis. In addition toPML-RARα, 4 alternative fusion partners forRARα in APL have been identified, includingPLZF (promyelocytic leukemia zinc finger) on chromosome 11, nucleophosmin (NPM) on chromosome 5, NuMA(nuclear mitotic apparatus protein) gene on chromosome 11, and signal transducer and activator of transcription 5b (STAT5b) on chromosome 17. Each of the APL fusion proteins blocks myeloid differentiation through inhibition of normal RARα-mediated transcription. The mechanism for apoptosis resistance in APL, however, is unknown. Apoptosis resistance in a number of hematopoietic and nonhematopoietic tumors has been linked to increased Stat3 activity. The ability of PML-RARα and other APL fusion proteins to augment Stat3 transcriptional activity supports the hypothesis that apoptosis resistance in APL may be mediated through the effects of APL fusion proteins on Stat3 and suggests the possibility that targeting Stat3 may be a useful adjunctive treatment strategy in this disease.
