A PMLRAR-ALPHA TRANSGENE INITIATES MURINE ACUTE PROMYELOCYTIC LEUKEMIA

The malignant cells of acute promyelocytic leukemia (APL) contain a re ciprocal chromosomal translocation that fuses the promyelocytic leukem ia gene (PML) with the retinoic acid receptor alpha gene (RAR alpha). To test the hypothesis that the chimera PMLRAR alpha plays a role in l eukemogenesis, we expressed a PMLRAR alpha cDNA in myeloid cells of tr ansgenic mice, PMLRAR alpha transgenic mice exhibited impaired neutrop hil maturation early in life, which progressed at a low frequency over the course of several months to overt APL, Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL, The APL recapitulated features of the human disease, including a response to retinoic acid, Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL i n mice, Our results demonstrate that PMLRAR alpha impairs neutrophil d ifferentiation and initiates the development of APL, The transgenic mi ce described here provide an apparently accurate model for human APL t hat includes clear evidence of tumor progression, The model should be useful for exploring the molecular pathogenesis of APL and the mechani sms of the therapeutic response to retinoic acid, as well as for precl inical studies of therapeutic regimens.