Transgenic expression of PML/RAR alpha impairs myelopoiesis

The translocation found in acute promyelocytic leukemia rearranges the promyelocytic leukemia gene (PML) on chromosome 15 with the retinoic acid receptor alpha (RAR alpha) on chromosome 17. This yields a fusion transcript, PML/RAR alpha, a transcription factor with reported dominant negative functions in the absence of hormone. Clinical remissions induced with all-trans retinoic acid (RA) treatment in acute promyelocytic leukemia are linked to PML/RAR alpha expression in leukemic cells. To evaluate the PML/RAR alpha role in myelopoiesis, transgenic mice expressing PML/RAR alpha were engineered. A full-length PML/RAR alpha cDNA driven by the CD11b promoter was expressed in transgenic mice. Expression was confirmed in the bone marrow with a reverse transcription PCR assay. Basal total white blood cell and granulocyte counts did not appreciably differ between PML/RAR alpha transgenic and control mice. Cell sorter analysis of Cd11b(+) bone marrow cells revealed similar CD11b(+) populations in transgenic and control mice. However, in vitro clonal growth assays performed on peripheral blood from transgenic versus control mice revealed a marked reduction of myeloid progenitors, especially in those responding to granulocyte/macrophage colony-stimulating factor. Granulocyte/macrophage colony-stimulating factor and kit ligand co-treatment did not overcome this inhibition. Impaired myelopoiesis in vivo was shown by stressing these mice with sublethal irradiation. Following irradiation, PML/RAR alpha transgenic mice, as compared with controls, more rapidly depressed peripheral white blod cell and granulocyte counts. As expected, nearly all control mice (94.4%) survived irradiation, yet this irradiation was lethal to 45.8% of PML/RAR alpha transgenic mice. Lethality was associated with more severe leukopenia in transgenic versus control mice. Retinoic acid treatment of irradiated PML/RAR alpha mice enhanced granulocyte recovery. These data suggest that abnormal myelopoiesis due to PML/RAR alpha expression is an early event in oncogenic transformation.