Modeling Acute Promyelocytic Leukemia in the Mouse: New Insights in the Pathogenesis of Human Leukemias

Acute promyelocytic leukemia (APL) is characterized by the expansion of malignant myeloid cells blocked at the promyelocytic stage of differentiation and is associated with reciprocal chromosomal translocations always involving the retinoic acid receptor α (RARα) gene on chromosome 17. As a consequence of the translocation, RARα variably fuses to the PML, PLZF, NPM, NuMA, and Stat5b genes (X genes), respectively, leading to the generation of RARα-X and X-RARα fusion genes. The aberrant chimeric proteins encoded by these genes, as well as the inactivation of the X and RARα functions, may exert a crucial role in leukemogenesis. To define the molecular genetics of APL and the contribution of each molecular event in APL pathogenesis, we have generated transgenic mice harboring X-RARα and/or RARα-X genes as well as mice where the various X genes have been inactivated by homologous recombination. Here we show that while the X-RARα fusion gene is crucial for leukemogenesis, the presence of RARα-X and the inactivation of X function are critical in modulating the onset as well as the phenotype of the leukemia.